KR20080070060A - Alpha;-HELIX MIMETICS AND METHOD RELATING TO THE TREATMENT OF CANCER STEM CELLS - Google Patents

Abstract

An alpha-helix mimetic compound is provided to be used in the preparation of a medicament for eradicating pathologic stem cells in cancer therapy, be useful for preparing a medicament for achieving the differentiation of pathologic stem cells by causing a switch from CBP/catenin to p300/catenin transcription in cancer therapy, inhibit CBP/catenin signaling in cancer stem cells by inhibiting CBP/catenin signaling in cancer stem cells thereby inducing differentiation of cancer stem cells and making them more susceptible to apoptosis induced by at least one specific pathway inhibitor and treat a cancerous condition by administering the same. A compound is represented by a formula(1), wherein A is (C=O)CHR3, or C=O; B is NR5 or CHR6: D is C=OHCHR7 or C=O; E is ZR8 or C=O; G is (XR9)n, (CHR10)(NR6), (C=O)XR12, C=NWR1, C=O, X(C=O)R13, X(C=O)NR13R14, X(SO2)R13, or X(C=O)OR13; W is Y(C=O), (C=O)NH, SO2, CHR14, (C=O)NR15, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing; Y is O or S; each X and Z is independently N or CH; n is 0 or 1; and R1, R2, R3, R4, R5, R6, R7, R8, R9 R10, R11, R12, R13, R14, and R15 are the same or different and independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers, salts, and prodrugs thereof, provided that where B is CHR6 and W is Y(C=O), (C=O)NH, SO2, CHR14, or (C=O)NR15, G cannot be CHR9, NR9, (C=O)CHR12, (C=O)NR12, or no atom at all. A pharmaceutical composition comprises the compound of the formula(1), a stereoisomer, a salt and a prodrug thereof, and a pharmaceutically acceptable carrier.

Description

α-HELIX MIMETICS AND METHOD RELATING TO THE TREATMENT OF CANCER STEM CELLS}

The present invention relates generally to α-helix analogue constructs and chemical libraries thereof. The present invention specifically relates to applications in the treatment of cancer and in particular cancer stem cells and pharmaceutical compositions comprising said α-helix analogues.

Despite the clone origin of many cancers, most major tumors exhibit notable cellular heterogeneity. Modern chemotherapy kills the vast majority of cells in tumors, but evidence indicates that cancer stem cells often survive. The cancer stem cell hypothesis assumes that only a very small number of cells in the tumors are tumor cells with infinite self-renewal capacity. This concept has important therapeutic implications and can explain why it is possible to treat many cancers until the tumor is no longer detected and nevertheless the cancers recur. There is a need in the art for compositions and methods to inhibit, reduce, and / or eliminate cancer stem cells from a patient.

The present invention also meets this need and is similar to the secondary structure of the α-helix region of biologically active peptides and proteins, and in particular optionally, structurally limited to disrupt β-catenin / CBP interactions. Providing constrained compounds provides additional related advantages.

This application claims priority to US Provisional Application No. 60 / 734,655, filed November 8, 2005, and is hereby incorporated by reference in its entirety.

Summary of the Invention

The present invention provides compounds having the following general formula (I), their stereoisomers, their salts, and their prodrugs:

Wherein A is-(C = O) -CHR ₃ -or-(C = O)-, B is NR ₅ -or -CHR _6- , and D is-(C = O)-(CHR ₇ )- Or-(C = O)-, E is-(ZR ₈ )-or-(C = O)-, G is-(XR ₉ ) n-,-(CHR ₁₀ )-(NR ₆ )-, -(C = O)-(XR ₁₂ )-,-(C = NWR ₁ )-,-(C = O)-, X- (C = O) -R ₁₃ , X- (C = O) -NR ₁₃ R ₁₄ , X- (SO ₂ ) -R ₁₃ , or X- (C = O) -OR ₁₃ , W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ )-, -CHR ₁₄ , (C = O)-(NR ₁₅ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X And Z is independently nitrogen or CH, n is 0 or 1; And R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is the same or different and is independently selected from an amino acid side chain moiety or a derivative thereof, a remainder of the molecule, a linker and a solid support, provided that B is Is CHR ₆ and W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ )-, -CHR ₁₄ , or (C = O)-(NR ₁₅ )- , G may be CHR ₉ , NR ₉ , (C═O) —CHR ₁₂ , (C═O) —NR ₁₂ , or no atoms at all.

In addition, the present invention is the R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ is amino C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl guanidino _2- C ₅ alkyl, amidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (where the substituents are amino, amidino , guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, C _{1- 4} alkyl, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, Independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidrazonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, Perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic independently selected from sulfuryl or at least one of the hydroxyl), naphthyl, substituted naphthyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkyl, amino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic independently selected from sulfuryl or at least one of the hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro Independently selected from one or more of carboxy, cyano, sulfuryl or hydroxyl ), Pyridyl, substituted pyridyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro- 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), pyrimidyl C _{1 - 4} alkyl, substituted pyrimidyl C _1-4 alkyl (where the pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl It is independently selected from one or more of the hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 -4} alkyl (where the triazine substituents are amino, amidino, obtain No gavel, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), imidazole C _{1 - 4} alkyl, substituted C _{1 -4} alkyl-imidazole (where imidazole substituent is amino, amidino, guanidyl gavel, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _1-4 dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl , C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl, or are independently selected from one or more of methyl), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl -NC _{0 - 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} a compound represented by the general formula (I) are independently selected from the group consisting of _2-alkyl, a salt thereof, and provides its prodrug.

Furthermore, in the present invention, A is-(CHR ₃ )-(C = O)-, B is-(NR ₄ )-, D is-(C = O)-, and E is-(ZR ₆ )-, G is-(C = O)-(XR ₉ )-and provides a compound of formula (I), a salt thereof, and a prodrug thereof, having the general formula (III):

Wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₉ , W and X are as defined in formula (I) above, Z is nitrogen or CH (where Z is CH, X is nitrogen) )to be.

In the present invention, A is -0-CHR _3- , B is -NR _4- , D is-(C = O)-, E is-(ZR ₆ )-, G is (XR ₇ ) _n -and the α-helix analog compounds of the present invention provide compounds of formula (I), salts thereof, and prodrugs thereof, wherein:

Wherein, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , R ₈ , W, X and n are as defined above, Y is -C = O,-(C = O) -O-,-(C = O) -NR ₈ , -SO _2- , or absent, Z is nitrogen or CH (n is 0 when Z is nitrogen, X is nitrogen and n is not 0 when Z is CH). In a preferred embodiment, R ₁ , R ₂ , R ₆ , R ₇ And R ₈ represents the remainder of the compound and R ₄ is selected from amino acid side chain moieties. In this case, when Z and X are each CH, R ₆ or R ₇ may be selected from amino acid side chain moieties.

Furthermore, in the present invention, A is-(C = O)-, B is-(CHR ₆ )-, D is-(C = O)-, E is-(ZR ₈ )-, and G is Is-(NH)-or-(CH ₂ )-, W is substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4, 5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, and the α-helix analog compound of the present invention has the following general formula (V) Provided are compounds of Formula (I), salts thereof, and prodrugs thereof:

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, J is nitrogen, oxygen, or sulfur, Z is nitrogen or CH, R ₁ , R ₂ , R ₆ , R ₈ And R ₁₃ is selected from the amino acid side chain moiety.

The present invention also provides compounds having the general formula (VI), stereoisomers thereof, salts thereof, and prodrugs thereof:

Wherein B is-(CHR ₂ )-or-(NR ₂ )-, E is-(CHR ₃ )-, V is-(XR ₄ )-or absent, and W is-(C = O)- (XR ₅ R ₆ ),-(SO ₂ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydro Oxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen, oxygen, or CH, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are selected from amino acid side chain moieties or derivatives thereof, the remainder of the molecule, linker and solid support.

Furthermore, the present invention is the R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, C _{1 - -} C _{1 4} di-alkyl amino, halogen, _{perfluoro-4-alkyl,} C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl Is hydroxy are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, C _{1 - - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), C _{1- 4} alkyl, C ₁ to ₄ dialkylamino, halogen, perfluoro bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro a C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _1-3 is independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where Substituents include amino, amidino, guanidino, hydrazino, Amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic sulfuryl or are independently selected from one or more of the hydroxyl), pyridyl C _{1 - 4} alkyl, C _{1 -4} alkyl-substituted pyridyl (where the pyridine substituents amino, amidino, guanidino, hydrazino, amino dryer Zonyl, C _{1 - 4} alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), pyrimidyl C _{1 - 4} alkyl, C _{1 -4} alkyl substituted pyrimidyl (where pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl- C _{1 -4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl are independently selected from at least one of the lock), imidazole C _{1 - 4} alkyl, substituted imidazole C _1-4 alkyl (where the imidazole substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _1-4 dialkylamino, C ₁ by a halogen, _perfluoro-4 alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one of the methyl It is independently selected from a), already Jolly carbonyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} general formula (I independently selected from the group consisting of ₂ alkyl ), Salts thereof, and prodrugs thereof. Furthermore, in the present invention, B is-(CH)-(CH ₃ ), E is-(CH)-(CH ₃ ), V is-(XR ₄ )-or absent, and W is substituted or unsubstituted. Substituted oxadiazoles, substituted or unsubstituted triazoles, substituted or unsubstituted thiadiazoles, substituted or unsubstituted 4,5 dihydrooxazoles, substituted or unsubstituted 4,5 dihydrothiazoles, or Substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen or CH, to provide a compound having the general formula (VII), salts thereof, and prodrugs thereof:

Wherein K is nitrogen, oxygen, or sulfur, L is a nitrogen, oxygen, - (CH) -, or - (CH ₂₎ - and, J is nitrogen, oxygen, or sulfur, R ₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, amidino C _{2 - 5} alkyl, C _{1 - 4} alkyl amidino _2- C ₅ alkyl, di-C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (where the substituents are amino, amidino, guanidino, hydrazino, amido drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano No, snow are independently selected from sulfuryl or at least one of the hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino , C _{1 - 4} Di-C _{1- 4} alkyl, alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), naphthyl naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _perfluoro-4 alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents is amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-alkyl amino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C ₁ part of _3-alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl Is selected as a site independent), pyridyl, substituted pyridyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1 - 4} dialkylamino, halogen , perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl C _{1 - 4} alkyl, substituted C _{1 -4} alkyl-pyridyl (pyridine wherein the substituent is amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, purple by Luo C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyrimidyl C _{1- 4} alkyl, pyrimidyl substituted C _{1 -4} alkyl (where the pyrimidine substituents are amino, amidino, guanidino, great Hydrazino, amido drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano no, sulfuryl or hydroxyl are independently selected from one or more of the hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 -4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} with di-alkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), imidazole C _{1 - 4} alkyl, optionally substituted imidazol-C _{1 -4} alkyl (wherein the substituent is an amino-imidazole , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, purple Lu A C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, are independently selected from hydroxyl or one or more of methyl), and Jolly already carbonyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _{1 - 5} alkyl-amino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 -} are independently selected from the group consisting of _{2-alkyl-4-alkyl} and 4-amino-cyclohexyl C _0.

The present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a salt thereof, and a prodrug thereof, and a pharmaceutically acceptable carrier.

Wherein A is-(C = O) -CHR ₃ -or-(C = O)-, B is NR ₅ -or -CHR _6- , and D is-(C = O)-(CHR ₇ )- Or-(C = O)-, E is-(ZR ₈ )-or-(C = O)-, G is-(XR ₉ ) n-,-(CHR ₁₀ )-(NR ₆ )-, -(C = O)-(XR ₁₂ )-,-(or absent)-,-(C = O)-, X- (C = O) -R ₁₃ , X- (C = O) -NR ₁₃ R ₁₄ , X- (SO ₂ ) -R ₁₃ , or X- (C = O) -OR ₁₃ , where W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ ) -, -CHR ₁₄ , (C = O)-(NR ₁₅ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4 , 5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X and Z Is independently nitrogen or CH, n is 0 or 1; And R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is the same or different and is independently selected from an amino acid side chain moiety or a derivative thereof, a remainder of the molecule, a linker and a solid support.

In addition, the present invention is the R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ is amino C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl guanidino _2- C ₅ alkyl, amidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (where the substituents are amino, amidino , guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, C _{1- 4} alkyl, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, Independently selected from one or more of nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidrazonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, Perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic independently selected from sulfuryl or at least one of the hydroxyl), naphthyl, substituted naphthyl (wherein the substituent is amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkyl, amino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic independently selected from sulfuryl or at least one of the hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro Independently selected from one or more of carboxy, cyano, sulfuryl or hydroxyl ), Pyridyl, substituted pyridyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro- 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), pyrimidyl C _{1 - 4} alkyl, substituted pyrimidyl C _1-4 alkyl (where the pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl It is independently selected from one or more of the hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 -4} alkyl (where the triazine substituents are amino, amidino, obtain No gavel, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), imidazole C _{1 - 4} alkyl, substituted C _{1 -4} alkyl-imidazole (where imidazole substituent is amino, amidino, guanidyl gavel, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _1-4 dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl , C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl, or are independently selected from one or more of methyl), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl -NC _{0 - 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} provides a pharmaceutical composition comprising a compound of formula (I) are independently selected from the group consisting of _2-alkyl. Furthermore, in the present invention, A is-(CHR ₃ )-(C = O)-, B is-(NR ₄ )-, D is-(C = O)-, and E is-(ZR ₆ ), G is-(C = 0)-(XR ₉ )-, and provides a pharmaceutical composition comprising a compound of Formula (I) having the structure of Formula (III):

Wherein Z is nitrogen or CH, provided that when Z is CH, X is nitrogen.

Further, in the present invention, A is -0-CHR _3- , B is -NR _4- , D is-(C = O)-, E is-(ZR ₆ )-, and G is (XR ₇ ) _n -wherein the α-helix analogue compound comprises a compound of Formula (I) having the following Formula (IV):

Wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , R ₈ , W, X and n are as defined above and Y is-(C = O)-,-(C = O)- O-,-(C = O) -NR ₈ , -SO _2- , or nothing, Z is nitrogen or CH (n is 0 when Z is nitrogen, X is nitrogen when Z is CH) n is not zero). In a preferred embodiment, R ₁ , R ₂ , R ₆ , R ₇ , and R ₈ represent a residue of the compound and R ₄ is selected from amino acid side chain moieties. In this case, when Z and X are each CH ₃ , R ₆ and R ₇ may be selected from amino acid side chain moieties. In the present invention, A is-(C = O)-, B is-(CHR ₆ )-, D is-(C = O)-, E is-(ZR ₈ )-, and G is -(NH)-or-(CH ₂ )-, W is substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 Dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, wherein the α-helix analogue compound of the present invention has the general formula (V) To provide a pharmaceutical composition.

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, J is nitrogen, oxygen, or sulfur, Z is nitrogen or CH, R ₁ , R ₂ , R ₆ , R ₈ And R ₁₃ is selected from the amino acid side chain moiety.

Furthermore, the present invention provides a pharmaceutical composition comprising a compound having the general formula (VI), a stereoisomer thereof, a salt thereof, and a prodrug thereof:

Wherein B is-(CHR ₂ )-or-(NR ₂ )-, E is-(CHR ₃ )-, V is-(XR ₄ )-or absent, and W is-(C = O)- (XR ₅ R ₆ ),-(SO ₂ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydro Oxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen, oxygen, or CH, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are selected from amino acid side chain moieties or derivatives thereof, the remainder of the molecule, linker and solid support. In this pharmaceutical composition, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _1-4 alkyl, amidino C _{2 - 5} alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, C _{1 - -} C _{1 4} di-alkyl amino, halogen, _{perfluoro-4-alkyl,} C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl Is hydroxy are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, C _{1 - - 4} alkyl, C _{1 - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), C ₁ to ₄ dialkylamino, halogen, perfluoro bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro a C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where Substituents are amino, amidino, guanidino, hydrazide , Amido drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, Description are independently selected from one or more of sulfuryl or hydroxyl), pyridyl C _{1- 4} alkyl, substituted C _{1 -4} alkyl-pyridyl (pyridine wherein the substituent is amino, amidino, guanidino, hydrazino, amido Dryer Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxylamine are independently selected from one or more of), pyrimidyl C _{1 - 4} alkyl, substituted pyrimidyl C _1-4 alkyl (where the pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino dryer Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 4} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl are independently selected from one or more of the hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _1-4 alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _perfluoro-4 alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), imidazole C _{1 - 4} alkyl, substituted imidazole C _{1 -4} alkyl (where the imidazole substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl , C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one of the methyl It is independently selected from a), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, _2- hydroxy-C ₅ alkyl, C _{1 - 5} alkyl-amino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1- 4-alkyl} and 4-amino-cyclohexyl-C _{0 -} are independently selected from the group consisting of _2-alkyl. In certain embodiments, B is-(CH)-(CH ₃ ), E is-(CH)-(CH ₃ ), V is-(XR ₄ )-or absent, and W is substituted or unsubstituted Substituted oxadiazoles, substituted or unsubstituted triazoles, substituted or unsubstituted thiadiazoles, substituted or unsubstituted 4,5 dihydrooxazoles, substituted or unsubstituted 4,5 dihydrothiazoles, substituted Or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen or CH, and the compound has the general formula (VII):

Wherein K is nitrogen, oxygen, or sulfur, L is a nitrogen, oxygen, - (CH) -, or - (CH ₂₎ - and, J is nitrogen, oxygen, or sulfur, R ₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, amidino C _{2 - 5} alkyl, C _{1 - 4} alkyl amidino _2- C ₅ alkyl, di-C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (where the substituents are amino, amidino, guanidino, hydrazino, amido drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano No, snow are independently selected from sulfuryl or at least one of the hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino , C _{1 - 4} Alkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), naphthyl , substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl , C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-alkyl amino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 -} the unit ₃ alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl Is independently selected), pyridyl, substituted pyridyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl C _{1 - 4} alkyl , substituted pyridyl C _{1 -4} alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro a C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyrimidyl C _{1- 4} alkyl, substituted a pyrimidyl C _{1 -4} alkyl (where the pyrimidine substituents are amino, amidino, guanidino, great La Gino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano no, sulfuryl or hydroxyl are independently selected from one or more of the hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 -4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} with di-alkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), imidazole C _{1 - 4} alkyl, optionally substituted imidazol-C _{1 -4} alkyl (wherein the substituent is an amino-imidazole , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro A C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, are independently selected from hydroxyl or one or more of methyl), and Jolly already carbonyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _{1 - 5} alkyl-amino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 -} are independently selected from the group consisting of _{2-alkyl-4-alkyl} and 4-amino-cyclohexyl C _0.

The present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of Compounds 1-2217, and at least one of Compounds 1-2217. The pharmaceutical composition may comprise an effective amount of the compound and a pharmaceutically acceptable carrier.

The compounds of the present invention can be used in the manufacture of a medicament for eradicating pathological stem cells in cancer treatment. The stem cells are stem cells of leukemia, and the stem cells may be derived from solid tumors, and the solid tumors may be derived from breast, brain, lung, colon, liver, and intestine.

A therapeutically effective amount of the compound is provided in an amount sufficient to cause cell death or inhibit proliferation and cause differentiation of stem cells in solid tumors or leukemias. Compounds of the Invention in the Treatment of Cancer It can be used in the manufacture of a medicament for achieving differentiation of pathological stem cells by causing the conversion from CBP / catenin transcription to p300 / catenin transcription. The catenin may be β-catenin or γ / p120-catenin.

The compound of the present invention, by inhibiting the CBP / catenin signal in cancer stem cells, thereby inducing the differentiation of cancer stem cells, thereby inducing cancer stem cells to apoptosis (apoptosis) induced by at least one specific pathway inhibitor As more sensitive, cancer stem cells can inhibit CBP / catenin signaling. Such specific pathways include EGFR pathways; Herceptin, Abl or Kit tyrosine kinase pathway (imatinib).

In addition, the compounds of the present invention are delivered to a subject orally, transdermally, intravenously, topically, inhaled, or rectally; Delivery may be by sustained release. The pharmaceutical composition may be administered by a method selected from the group consisting of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, and suppositories.

Furthermore, there is provided a method of treating a cancerous condition by administering at least one compound or pharmaceutical composition of the present invention, wherein the cancerous condition is acute lymphocytic leukemia, acute nonlymphocytic leukemia, minor Renal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, skin T cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukaemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or non-small cells), malignant Peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, Pancreas Intestinal cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, vulvar cancer of the vulva, and Wilm's tumor.

Furthermore, the present invention includes culturing stem cell cultures with at least one compound of the present invention that inhibits CBP-β-catenin interaction and thereby causes differentiation of stem cells, prior to transplantation into a mammalian subject. Provided are methods for removing teratoma-forming stem cells.

The present invention also provides a pharmaceutical composition for use in the manufacture of a medicament for eradicating pathological stem cells in cancer treatment.

1A-Z show the chemical structures of Compounds 1-200.

2A-2AD show the chemical structures of Compounds 201-400.

3A-3AC show the chemical structures of Compounds 401-600.

4A-4Y show the chemical structures of Compounds 601-800.

5A-5Y show the chemical structures of Compounds 801-1000.

6A-6Y show the chemical structures of Compounds 1001-1200.

7A-7Z show the chemical structures of Compounds 1201-1400.

8A-8AC show the chemical structures of Compounds 1401-1600.

9A-9AE show the chemical structures of Compounds 1601-1800.

10A-10AA show the chemical structures of Compounds 1801-2000.

11A-11AA show the chemical structures of Compounds 2001-2200.

12A-12C show the chemical structures of the diastereomers and enantiomers of Compounds 2203-2217.

Figures 13A-C. 13A shows the structure of compound ASN 06387747. 13B shows the structure of compound ICG-001 (red). 13C shows the structure of superimposed ASN 06387747 (green) and ICG-001 (red). In certain embodiments of the invention, each compound has three pharmacophore rings. The distance measured from the center of each drug action ring may be based on the conformation calculated by the flexible alignment calculations. As shown in this figure, the distance between F1 and F4 is approximately 9.6 kPa, the distance between F1 and F6 is approximately 9.2 kPa, and the distance between F4 and F6 is approximately 10.3 kPa.

14A-C show drug sensitivity As compared to counterparts, the levels of β-catenin in the cytoplasm and nucleus were measured by immunoblotting (FIG. 14A), as measured by immunofluoresence microscopy (FIG. 14A). 14B). Increased nuclear β-catenin was blocked by the use of dominant negative TCF4 constructs (FIG. 14C).

15A-E show that in MES-SA cells, Wnt3a but not Wnt5a increases luciferase activity blocked by cotransfection with dominant negative TCF4 constructs (FIG. 15A ). Wnt5a regulatory medium does not show enhanced expression of the MDR-1 / luciferase reporter construct (FIG. 15B). MDR-1 wild-type HCT-116 cells and Hβ18 (KO / *) cells are shown in FIG. 15C (MDR-1 / luciferase activity) and FIG. 15D (RT-PCR). Recruitment of TCF4 and β-catenin to the MDR-1 promoter is shown in FIG. 15E.

16A-E show the effect of ICG-001 on the transcriptional regulation of MDR-1 gene in MES-SA cells: MDR-1 / luciferase activity (16A); MDR-1 protein expression by immunofluorescence (16B) and immunoblotting (16C); Message level by RT-PCR in MES-SA / Dx5 cells (16D) and K562 cells (16E).

17A-C show MDR-1 transcriptional regulation in HCT116 cell line: MDR-1 / luciferase expression (17A); Effect of ICG-001 (17B); And occupancy blockage of the MDR-1 promoter by CBP (17C).

18A-E show mRNA levels of endogenous CBP coactivators compared to p300 (FIG. 18A); Level of CBP (FIG. 18B); association of p300 with β-catenin (FIG. 18C); level of p300 (FIG. 18D); And effect of p300 siRNA (FIG. 18E).

19A-F compare K562 cells and MES-SA / Dx5 cells: growth rates (19A, 19B); Message levels (19C, 19D) for survivin and cyclin D1; And protein levels (19E, 19F) for sorbvin and cyclin D1.

20 RT-PCR shows increased expression of Oct4, hTert, Bmi-1 and ABCG-2 in MES-SA / Dx5 cells and K562 cells. Protein levels for Oct4 and CD133 were increased in these cell lines.

Figures 21A-D. 21A shows that ICG-001 in combination with each chemotherapeutic agent is more effective at reducing cell proliferation / viability than the chemotherapeutic agent alone or ICG-001 alone. 21B: ICG-001 has no effect on CD34 + normal hematopoeitic cells. Figure 21C: ICG-001 * aka PRI-004 completely blocks colony formation at 500 nM concentration. 21D shows that the combination treatment of ICG-001 and Imatinib reduced colony forming units than either alone medication.

22A-E. The effect of ICG-001 at different doses with or without imatinib is shown in FIGS. 22A and 22B. 22C and 22D: β-catenin, BMI-1, MDR-1, ABCG1, sorbvin, and sorbine in CD34 + cells isolated from bone marrow of CML blast crisis patients not receiving Imatinib RT-PCR Analysis for Splice Modified Delta Ex3. Reference is CD34- cells from the same patient. Figure 22D: Colony formation is assessed using CD34 + cells from blast crisis CML patients who do not administer imatinib. 22E: Hematoxylin and eosin staining for CD34 + blasts were treated with 0.5 μM imatinib alone (top) or with 0.5 μM imatinib with 5 μM of ICG-001.

FIG. 23 shows the sensitivity of IGROV-1 (FIG. 23A), A2780 (FIG. 23B), and CP70 (FIG. 23C) to ICG-001 as tested in replicate experiments using different concentrations.

Figure 24 shows the sensitivity of ovarian cell lines A2780 and CP70 to ICG-001.

25. Compared with ICG-001, FIG. 25 shows that increasing concentrations of compounds PRI-001, PRI-002, PRI-003, PRI-004, PRI-005, and PRI-006 on SW480 cells are effective. Indicates.

FIG. 26 shows pluc-6270 expression (luciferase) in SW480 cells treated with various concentrations of ICG-001, PRI-003, and PRI-004.

27 shows the chemical structures of Compounds 2203-2217.

Detailed description of the invention

The present invention relates to the secondary structure of the α-helix region of biological peptides and proteins for the inhibition and / or eradication of cancer cells, particularly cancer cells with significant self-renewal potential, such as cancer stem cells (herein "α Structurally constrained compounds and chemical libraries thereof.

Significant progress has been made in the development of molecular target drugs for cancer, such as IGleevec, for the treatment of chronic CML, but these drugs often fail. It is clear that eradication of cancer stem cells, that is, eradication of problem roots, is required for new drugs.

Several similarities can be found between somatic stem cells and cancer stem cells (Pardal et al. Nat. Rev. Cancer. 3, 895 , 2003). Both somatic and cancer stem cells are endowed with self-renewal and differentiation capacity. However, important differences exist. Somatic stem cells differentiate into normal tissues, while cancer stem cells differentiate abnormally (Reya et al, Nature 2001, 414, 105-111). Despite the clonal origin of many cancers, most major tumors exhibit notable cellular heterogeneity. Therefore, modern chemotherapy kills the majority of cells in tumors, but it is believed that cancer stem cells often remain. ATP-binding cassette (ABC) multidrug resistant (MDR) transporters are believed to play an important role in the protection of cancer stem cells from chemotherapy (Dean et al, Nat. Rev. Cancer 5, 275, 2005). Overexpression of P-glycoprotein (Pgp), various energy-dependent efflux pumps of chemotherapeutic agents, and the consequences of combination drug-resistant tumor cells were first described 20 years ago (Ling V. Cancer Chemother. Pharm. 40, S3-8, 1997; Sharom, FJJ Membr. Biol. 160, 161-175, 1997). MDR1 is a "TATA-less" gene and belongs to a group of proteins that lack a censensus TATA box in the proximal promoter region of the gene (Cornwell, MM Cell Growth Differ. 1, 607-). 615, 1990). Cells selected for cell resistance to drugs frequently exhibit structural overexpression of MDR1. In addition, the outflow of Hoechst 33342 from normal hematopoietic cells demonstrates the "side population (SP (+)") of negatively staining cells enriched for primitive progenitor cells (Feuring-Buske M). , et al., Blood, 15: 3882-9, 2001).

Mutations in the adenomatous polyposis coli (APC), which occurs early in the majority of hereditary and sporadic colorectal cancers, are complex with members of the T-cell factor (TCF) / lymphoid enhancer (LEF-1) family of transcription factors Induces nuclear accumulation of β-catenin, which forms (8). To generate a transcriptionally active complex, β-catenin is expressed in the transcriptional coactivator Creb-binding protein (CBP) or its closely related homolog, p300 (as well as other components of basic transcription machinery). 9, 10). The MDR1 promoter contains several TCF / LEF binding sites between positions-275 and -1813. The association between APC mutation and enhanced MDR-1 expression by TCF / β-catenin induced transcription is described (Yamada T., et al. Cancer Res. 60, 4761 -4766, 2000).

Despite similar patterns of CBP and p300 high degree of homology and expression, it is clear that they play a unique and completely different role in gene regulation. The data disclosed herein were obtained using siRNA, ChIP analysis and chemogenomic tool ICG-001, which ICG-001 selectively disrupts β-catenin / CBP interactions but does not correspond to the corresponding β. Does not interfere with the interaction of catenin / p300 (Emami et al PNAS, 2004), thereby interfering with a subset of gene expression regulated by Wnt / β-catenin, including survivin (Ma et al Oncogene 2005). The present disclosure demonstrates that TCF / β-catenin / CBP induced gene expression is essential for MDR-1 transcription. Furthermore, on a broader background, the disclosure indicates that the CBP / β-catenin induced transcription cassette is critical for the expression of a "cancer stem cell-like" profile.

Embryonic stem cells can proliferate immediately in vitro and in vivo. In vivo ( In in vivo ), if they are injected subcutaneously, intramuscularly, or testicles, they can form teratocarcinoma-like tumors in mature mice (Thomson, JA, et al., Science 282: 1145-7: 1998; Odorico, JS , Stem Cells 19: 193- 204, 2001; Chung, Y., et al., Nature 439: 216-9, 2006). Thus, hES cell-based therapy can induce unwanted tumor formation.

In order to decontaminate the implants with residual undifferentiated ES cells, two different approaches have been reported. In one case, ES cell-specific expression is used in engineered cell lines made of compounds toxic to undifferentiated ES cells and the culture conditions are altered to allow expression. This approach removes mouse ES cells from the mixed cell population prior to transplantation (Billon, N., et al., J Cell Sci, 115: 3657-65, 2002), and after transplantation the differentiated stem cells Was used to express suicide genes (Schuldiner, M., J., Stem Cells 21: 257-65, 2003). In another approach, mixed cell populations are treated with ceramide analogue N-oleoyl serinol (S18) to selectively induce apoptosis of ES cells (Bieberich, E). , et al., J Cell Biol. 167: 723-34, 2004). In this case, formation of the teratocarcinoma accompanying transplantation of mixed populations containing both ES stem and ES-derived neural stem cells was hindered (Bieberich, E., et al., J Cell Biol 167: 723-34, 2004).

The compounds and methods disclosed herein provide another option for removing teratoma-forming stem cells prior to transplantation. Advantageously, the treatment used a trace that is not toxic to humans at the dosage to be used.

Confirmation of the synthetic and structurally constrained α-helix analogs and their application to diseases is described by Walensky, LD et al Science 305, 1466, 2004; and Klein, C. Br . J, Cancer . 91, 1415, 2004. This publication, in combination with other chemotherapeutic agents, targeting cancer stem cells by antagonizing CBP / β-catenin interactions, suggests that transcription of anti-apoptotic genes, such as survivin, may be inhibited. Reducing not only eliminates cancer stem cells that are resistant to common chemotherapy, but further demonstrates that it has the additional effect of killing other cancer cells normally sensitive to chemotherapy.

As shown in detail in the Examples, the compound ICG-001 disclosed herein reduced MDR-1 / luciferase activity in doxorubicin-resistant ovarian sarcoma lines MES-SA / Dx5 and CML induced cell lines K562. In these cell lines, there is an increase in the levels of β-catenin in the cytoplasm and nucleus. This activated Wnt / β-catenin pathway doubles the activation of multiple resistance genes in cell lines.

 By reducing MDR-1 / luciferase activity, ICG-001 was one candidate for testing for patient CML cells. The examples further show that ICG-001 in combination with imatinib reduces total colony forming units compared to either drug alone. Morphological testing indicated that the treated colonies had increased differentiation.

In addition to being effective against ovarian sarcoma and CML induced cells, ICG-001 reduced stem cell markers in cells to obtain other ovarian cell lines and melanoma B16 cells. Several other compounds, including ICG-001 and PRI-001, PRI-002, PRI-003, PRI-004, PRI-005, and PRI-006, are derived from SW480 cells, intestinal carcinoma of the gut. Induced cell lines inhibited CBP and β-catenin interactions.

The wide range of cancers that can be treated with the compounds disclosed herein is consistent with the role of β-catenin in several cancer-related outcomes. These include expression of bovine bins, expression of MDR-1, and maintenance of cancer stem cell populations.

Thus, the compounds and methods herein include acute lymphocytic leukemia, acute nonlymphocytic leukemia, adrenal cortical cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, skin T cell lymphoma, endometrium Cancer, Esophageal cancer, Ewing's sarcoma, Gallbladder cancer, Hairy cell leukaemia, Head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, Kidney cancer, Liver cancer, Lung cancer (small cell And / or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-hodgkin's lymphoma, osteosarcoma, ovarian cancer , Ovarian (germ cell) cancer, pancreatic cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms,Including the gungam, vaginal, well munam (cancer of the vulva), and Will reumjeu tumors (Wilm's tumor) (not limited to) it is suitable for the treatment of cancer.

The α-helix analog constructs of the present invention are useful as bioactive agents, including, but not limited to, use as diagnostics, prophylactic and / or therapeutic agents. The α-helix analog structure library of the present invention is useful in the identification of such bioactive agents. In the practice of the present invention, the library may contain individual α-helix structures (also referred to herein as "members") ranging from tens to hundreds to thousands (or more).

In one embodiment of the present invention, α-helix analog structures having the following general formula (I) and stereoisomers thereof are disclosed:

Wherein A is-(C = O) -CHR ₃ -or-(C = O)-, B is NR ₅ -or -CHR _6- , and D is-(C = O)-(CHR ₇ )- Or-(C = O)-, E is-(ZR ₈ )-or-(C = O)-, G is-(XR ₉ ) n-,-(CHR ₁₀ )-(NR ₆ )-, -(C = O)-(XR ₁₂ )-,-(C = NWR ₁ )-,-(C = O)-, X- (C = O) -R ₁₃ , X- (C = O) -NR ₁₃ R ₁₄ , X- (SO ₂ ) -R ₁₃ , or X- (C = O) -OR ₁₃ , W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ )-, -CHR ₁₄ , (C = O)-(NR ₁₅ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X And Z is independently nitrogen or CH, n is 0 or 1; And R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is the same or different and is independently selected from an amino acid side chain moiety or a derivative thereof, a remainder of the molecule, a linker and a solid support.

More specifically, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl guanidino _2- C ₅ alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl, amidino C _2-5 alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl addition Hydroxide are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-C _{1- 4} alkyl, alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), bis phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1 -} to ₄ dialkylamino, halogen, perfluoro C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where the substituents Amino, amidino, guanidino, hydrazino, Mithraic Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl are independently selected from one or more of the lock), pyrimidyl C _{1 - 4} alkyl, C _{1 -4} alkyl substituted pyrimidyl (where pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} with di-alkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl ₁ -C _-4 alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl , C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), imidazole C _{1 - 4} alkyl, imidazole substituted already C _{1 - 4} alkyl (imidazol substituent wherein is amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4-di-C 1} to alkyl, amino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one of the methyl Are independently selected from a), imidazolinyl C _{1- 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _{1 -} C _{5 alkylamino-2- 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} are independently selected from alkyl and 4-amino cyclohexyl group consisting of C _{2 0-} alkyl.

In one embodiment, R ₁ , R ₂ of E And R ₇ , R ₈ of R ₆ and G And R ₉ is the same or different and represents the remainder of the compound, wherein R ₃ of A, R _{4 of} B, or R ₅ of D is selected from an amino acid side chain portion or a derivative thereof. As used herein, the term “residue of the compound” refers to R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ And / or any moiety, agent, compound, support, molecule, linker, amino acid, peptide, or protein covalently bonded to the α-helix analog structure at the R ₉ position. The term also includes amino acid side chain moieties and derivatives thereof.

As used herein, the term “amino acid side chain portion” refers to any amino acid side chain portion present in a natural protein, including but not limited to the natural amino acid side chain portion identified in Table 1. Other amino acid side chain portions of the invention include, but are not limited to, side chain portions of 3,5-dibromotyrosine, 3,5-diiodotyrosine, hydroxylysine, γ-carboxyglutamate, phosphotyrosine and phosphoserine Is not). In addition, glycosylated amino acid side chains including, but not limited to, glycated threonine, serine and asparagine can also be used in the practice of the present invention.

Amino acid side chain portion Amino acid side chain portion amino acid -H Glycine -CH ₃ Alanine -CH (CH ₃ ) ₂ Valine -CH ₂ CH (CH ₃ ) ₂ Leucine -CH (CH ₃ ) CH ₂ CH ₃ Isoleucine -(CH ₂ ) ₄ NH ₃ ⁺ Lee Sin -(CH ₂ ) ₃ NHC (NH ₂ ) NH ₂ ⁺ Arginine Histidine -CH ₂ COO ^- Aspartic acid -CH ₂ CH ₂ COO ^- Glutamic acid -CH ₂ CONH ₂ Asparagine -CH ₂ CH ₂ CONH ₂ Glutamine Phenylalanine Tyrosine Tryptophan -CH ₂ SH Cysteine -CH ₂ CH ₂ SCH ₃ Methionine -CH ₂ OH Serine -CH (OH) CH ₃ Threonine Proline Hydroxyproline

In addition to the natural amino acid side chain moieties, the amino acid side chain moieties of the present invention also include various derivatives thereof. As used herein, “derivatives” of amino acid side chain moieties include modifications and / or changes of natural amino acid side chain moieties. For example, the amino acid side chain portions of alanine, valine, leucine, isoleucine and phenylalanine can generally be classified as lower alkyl, aryl, or arylalkyl moieties. Derivatives of amino acid side chain moieties include other straight or branched chain, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated lower alkyl, aryl, or arylalkyl moieties.

As used herein, the "lower alkyl moiety" includes 1-12 carbon atoms, the "lower aryl moiety" contains 6-12 carbon atoms and the "lower aralkyl moiety" contains 7-12 carbon atoms. Thus, in one embodiment, the amino acid side chain derivative is C _{1 -12} alkyl, C _{6 -12} aryl, and C _{7 -12} is selected from an aryl alkyl, a further preferred embodiment the C _{1 -7} alkyl, C _{6 -10} aryl and C _{-11 7} is selected from arylalkyl.

The amino acid side chain derivatives of the present invention further include substituted derivatives of lower alkyl, aryl, and arylalkyl moieties, wherein the substituents are selected from, but are not limited to, one or more of the following chemical moieties: -OH, -OR , -COOH, -COOR, -CONH ₂ , -NH ₂ , -NHR, -NRR, -SH, -SR, -SO ₂ R, -SO ₂ H, -SOR and halogen (including F, Cl, Br and I Wherein, the presence of each R is independently selected from straight or branched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated lower alkyl, aryl or aralkyl moiety. do. Moreover, the cyclic lower alkyl, aryl, and arylalkyl moieties of the present invention are thiophene, pyrrole, furan, imidazole, oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine, pyrimidine, Heterocyclic compounds such as purine, quinoline, isoquinoline, and carbazole, as well as naphthalene. Amino acid side chain derivatives further include heteroalkyl derivatives of lower alkyl and aralkyl moieties, including but not limited to alkyl and aralkyl phosphonates and silanes.

Representative R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ moieties are especially -OH, -OR, -COR, -COOR, -CONH ₂ , CONR, -CONRR, -NH ₂ , And include, but are not limited to, -NHR, -NRR, -SO ₂ R, and -COSR, wherein the presence of each R is as defined above.

In another embodiment, in addition to being an amino acid side chain moiety or a derivative thereof (or the remainder of the compound in the case of R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ ), R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ , or R ₉ may be a linker to promote binding of the compound to another moiety or compound. For example, the compounds of the present invention can be combined with one or more known compounds, such as biotin, for diagnostic or screening assays. Further, R ₁ , R ₂ , R ₅ , R ₆ , R ₇ , R ₈ , or R ₉ may be a linker to bind the compound to a solid support (eg, a support used in solid phase peptide synthesis), or It can be the support itself. In this embodiment, the bond to another moiety or compound, or solid support, is R ₁ , R ₂ , R ₇ or R ₈ position is preferred, and R ₁ or R ₂ position is more preferred.

In this embodiment, A is-(C = O)-(CHR ₃ )-, B is -NR ₄ , D is-(C = O)-, E is-(ZR ₆ )-, G is-(C = 0)-(XR ₉ )-, and the α-helix analogue compound of the present invention has the following general formula (III):

Wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , R ₈ , W and X are as defined above and Y is-(C = O)-,-(C = O) -O- ,-(C═O) —NR ₈ , —SO ₂ —, or nothing, and Z is nitrogen or CH (wherein Z is CH, X is nitrogen). In one preferred embodiment, R ₁ , R ₂ , R ₆ , R ₇ , and R ₈ are Remainder of the compound, R ₄ is selected from amino acid side chain moiety. In a more particular embodiment, A is -0-CHR _3- , B is -NR _4- , D is-(C = 0)-, E is-(ZR ₆ )-and G is (XR ₇ ) _n- , the α-helix analogue compound of the present invention has the following general formula (IV):

Wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , W, X and n are as defined above, Z is nitrogen or CH (when Z is nitrogen, n is 0 and Z is CH , X is nitrogen and n is not zero). In one preferred embodiment, R ₁ , R ₂ , R ₆ , and R ₇ represent a residue of the compound, and R ₄ is selected from amino acid side chain moieties. In this case, when Z and X are CH, respectively, R ₆ and R ₇ can be selected from amino acid side chain moieties.

In an embodiment of structure (I), A is — (C═O) —, B is — (CHR ₆ ) —, D is — (C═O) —, and E is — (ZR ₈ ) — And G is-(NH)-or-(CH ₂ )-and W is substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, and the α-helix analog compound of the present invention is represented by the following general formula (V Has:

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, J is nitrogen, oxygen, or sulfur, Z is nitrogen or CH, R ₁ , R ₂ , R ₆ , R ₈ And R ₁₃ is selected from the amino acid side chain moiety.

An alternative embodiment of the invention relates to compounds having the general formula (VI) and stereoisomers thereof:

Wherein B is-(CHR ₃ )-or-(NR ₃ )-, E is-(CHR ₄ )-, V is-(XR ₅ )-or absent, and W is-(C = O)- (XR ₆ R ₇ ),-(SO ₂ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydro Oxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen, oxygen, or CH, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently selected from amino acid side chain moieties or derivatives thereof, the remainder of the molecule, linkers and solid supports.

In an embodiment of Formula (VI), V is-(XR ₅ )-or absent, W is substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole , Substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen or CH, The compound has the general formula (VII):

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, J is nitrogen, oxygen, or sulfur, and R ₂ And R ₅ is as defined above.

In a preferred embodiment of the invention, R ₂ in structures I to VII comprise aromatic ring substituents such as phenyl or naphthyl groups substituted with basic moieties such as primary or secondary amines. The aromatic ring substituent may also be a hetero cycle such as purine or indole. In addition, some embodiments of the present invention provide aromatic ring substituents that may be substituted with one or two halogen moieties.

A feature of many α-helix analog compounds may be referred to as specific, spatially-defined orientation pharmacophore rings, referred to as “optimized chemical space”. To provide scaffolding where three hydrophobic functional groups are located. The optimized chemical space may be a triangle with the center of three functional groups forming the three vertices of the triangle. One example of an optimized chemical space is that the length of the three sides of the triangle is about 9.6 ± 0.5 Angstroms (hereinafter referred to as “Å”), 9.2 ± 0.5 mm 3, and 10.3 ± 0.5 mm 3. Figure 13 shows two overlapping structures with three such drug action end rings forming a triangle in space. Many other compounds represent this optimized chemical space and such compounds can be considered within the scope of the present invention.

Compounds of formula (I) of the invention have one or more asymmetric carbons depending on their substituents. For example, when the compound of formula (I) contains one or more asymmetric carbons, there are two kinds of optical isomers when the number of asymmetric carbons is one, and four kinds of when the number of asymmetric carbons is two, There exist optical isomers and two kinds of diastereomers. Pure stereoisomers, including optical isomers and diastereomers, any mixtures, racemates, and stereoisomers are all within the scope of the present invention. Mixtures such as racemates may sometimes be desirable in view of ease for production.

When the compound of the general formula (I) of the present invention contains a basic functional group such as an amino group, or the compound of the general formula (I) of the present invention contains an aromatic ring (for example, a pyridine ring) which is basic in itself. If so, the compounds can be converted to pharmaceutically acceptable salts (inorganic acid salts such as hydrochloric acid and sulfuric acid or organic acid salts such as acetic acid and citric acid) by known methods. When the compound of the general formula (I) of the present invention contains an acidic functional group such as a carboxyl group or a phenolic hydroxyl group, the compound is a pharmaceutically acceptable salt (sodium, ammonia, etc.) by a known method. Inorganic salts, or organic salts such as triethylamine). When the compound of general formula (I) of the present invention contains prodrugable functional groups such as phenolic hydroxyl groups, the compound may be prepared by a known method. For example, acetylate or phosphonate). Any pharmaceutically acceptable salts and precursors are all within the scope of this invention.

The various compounds disclosed by the present invention can be purified by known methods such as recrystallization and various chromatography techniques (column chromatography, flash column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC)).

The α-helix analogue constructs of the invention can be prepared by using appropriate starting component molecules (hereinafter referred to as “constituent fragments”). In sum, in the synthesis of α-helix analogue structures having the general formula (II), the first and second constituent fragments are paired to form a combined first-second intermediate, and if necessary, third and / or The fourth constituent fragments are paired to form a bound third-fourth intermediate (or, if commercially available, a single third intermediate can be used), and the bound first-second intermediate and third-fourth By mating intermediates (or third intermediates), the closed first-second-second-third intermediate (or first-second-third intermediate) is obtained to obtain the α-helix analog structure of the present invention. to provide. Optionally, the α-helix analogue construct of formula (II) can be prepared by pairing the individual constituent fragments sequentially step by step in solution or by solid phase synthesis, which is usually carried out in solid phase peptide synthesis.

Within the context of the present invention, the "first constituent fragment" has the general formula S1:

Wherein R ₂ is as defined above and R is a protecting group suitable for use in peptide synthesis. Suitable R groups include alkyl groups, and in preferred embodiments, R is a methyl group. This first constituent fragment is substituted by reductive amination or by substitution of H ₂ NR ₂ from CH (OR) ₂ -CHO or CH (OR) ₂ -CH ₂ -Hal, where Hal represents a halogen atom. It can be easily synthesized by the reaction.

The "second constituent fragment" of the present invention has the general formula (S2):

Wherein L ₁ is a carboxyl-activating group such as a halogen atom, R ₃ , R ₄ are as defined above, and P is a suitable amino protecting group for use in peptide synthesis. Preferred protecting groups are t-butyl dimethylsilyl (TBDMS), t-butyloxycarbonyl (BOC), methyloxycarbonyl (MOC), 9H-fluorenylmethyloxycarbonyl (FMOC), and allyloxycarbonyl ( Alloc). When L is -C (O) NHR, -NHR may be a carboxyl protecting group. N-protecting amino acids are commercially available. For example, FMOC amino acids are commercially available from various sources. Conversion of such compounds to the second constituent fragment of the present invention can be readily accomplished by activating the carboxylic acid group of the N-protected amino acid. Properly activated carboxylic acid groups are acid halides in which X is a halide such as chloride or bromide, acid anhydrides in which X is an acyl group such as acetyl, N-hydroxy succinimide ester and pentafluorophenyl ester Reactive esters, and other activated intermediates such as active intermediates formed in coupling reactions using carbodiimides such as dicyclohexylcarbodiimide (DCC).

In the case of azido derivatives of amino acids that act as second constituent fragments, such compounds are prepared by the reactions disclosed in Zaloom et al . ( J. Org . Chem . 46: 5173-76, 1981). It can be prepared from.

The "third component fragment" of the present invention has the general formula (S3):

Wherein, G, E and L ₁ are as defined above. Suitable third component fragments are commercially available from various sources or can be prepared by methods known in organic chemistry.

More specifically, the α-helix analog structure of the present invention of general formula (II) reacts the first component fragment with the second component fragment to obtain a bound first-second intermediate, and then binds first-second The intermediates are reacted sequentially with the third constituent fragment to make the combined first-second-second-third intermediate, and the intermediates are cyclized to obtain α-helix analog structures.

General synthesis of α-helices having structure I ′ can be carried out by the following technique. As shown below, the first constituent fragment 1 is bound to the second constituent fragment 2 using a binding reagent such as a phosgene, and after N-deprotection, the bound first-second intermediate (1-2) is obtained.

Wherein, R ₁ , R ₂ , R ₄ , R ₇ , Fmoc, Moc and X are as defined above and Pol represents the polymer support.

Synthesis of representative constituent fragments of the invention is described in the Examples.

The α-helix analogue structures of Formulas (III) and (IV) can be prepared by techniques similar to the synthesis of the unit components described above, with the appropriate modification of the constituent fragments.

As noted above, the reverse-turn analogues of USP 6,013,458 to Kahn et al. Are useful as bioactive agents such as diagnostics, prophylactic and therapeutic agents. The opiate receptor binding activity of representative reverse-turn analogs is shown in Example 9 of US Pat. No. 6,013,458, where the reverse-turn analogs of the invention show that radiolabeled enkephalin derivatives bind to δ and μ opiate receptors. It has been found to inhibit effectively, and its data demonstrate the utility of such reverse-turn analogs as receptor agonists and potential analgesics.

The α-helix analog constructs of the present invention are useful as bioactive agents such as diagnostics, prophylactic and therapeutic agents.

Therefore, since the compounds according to the present invention are α-helix analogue structures, they may be useful for modulating cellular signaling transcription factor related peptides in warm blooded animals, including administering to the warm blooded animals an effective amount of a compound of formula (I). Can be. In addition to being useful for the treatment of humans, the compounds of the present invention may also be used for the treatment of veterinary mammals, including pet and farm animals such as, but not limited to, dogs, cats, horses, cattle, sheep, and pigs. useful for treatment).

Furthermore, the α-helix analog constructs of the present invention may also be effective in inhibiting transcription factor / coactivator and transcription factor corepressor interactions.

In another aspect of the present invention, libraries containing the α-helix analog structures of the present invention are disclosed. Once assembled, the libraries of the present invention can be screened to identify individual members with bioactivity. Such screening of a library for bioactive members may involve, for example, evaluating the binding activity of the members of the library or evaluating the impact of the library members on functional evaluation. Screening is normally accomplished by contacting a library member (or subset of library members) with a target of interest, for example, an antibody, enzyme, receptor or cell line. Library members that can interact with the target of interest are referred to herein as "bioactive library members" or "bioactive analogs". For example, bioactive analogs are library members that can bind to antibodies or receptors, inhibit enzymes, or elicit or antagonize functional responses associated with, for example, cell lines. In other words, the screening of libraries of the present invention determines which library members can interact with one or more biological targets of interest. In addition, if interaction occurs, bioactive analogs (or analogs) can be identified from library members. Identification of a single (or limited number) bioactive analog (s) from the library yields an α-helix analog construct that is itself biologically active and useful as a diagnostic, prophylactic or therapeutic agent, which is also leading in the art. It can be used to significantly advance the identification of compounds.

In another aspect of the invention, a method for building libraries is disclosed. Traditional combinations of chemical techniques (see Gallop et al . , J. Med . Chem . 37: 1233-1251, 1994) allow a huge number of compounds to be prepared quickly by sequential binding of reagents to the basic molecular backbone. Combination techniques have been used to construct peptide libraries derived from natural amino acids. For example, by taking 20 mixtures of 20 suitably protected different amino acids and combining each with one of the 20 amino acids, 400 (ie 20 ² ) dipeptide libraries are made. Repeating this procedure seven times prepares a peptide library of about 26 billion (ie 20 ⁸ ) octapeptides.

In particular, the synthesis of peptide analogs of the library of the present invention can be accomplished using known peptide synthesis techniques, for example the general scheme of the [4,4,0] α-helix analog library as follows:

Synthesis of peptide analogs of the libraries of the present invention was accomplished by known techniques using the FlexChem Reactor Block with 96 well plates. 'Pol' in the above scheme represents bromoacetal resin (Advanced ChemTech), the detailed procedure is described below.

Step 1

A solution of R ₂ -amine in bromoacetal resin (37 mg, 0.98 mmol / g) and DMSO (1.4 mL) was placed in a Robbins block (FlexChem) with 96 well plates. The reaction mixture was shaken at 60 ° C. for 12 hr using a rotary oven [Robbins Scientific]. The resin was washed with DMF, MeOH and DCM.

Step 2

A solution of available Fmoc hydrazine amino acids (4 equiv.), PyBop (4 equiv.), HOAt (4 equiv.), And DIEA (12 equiv.) In DMF was added to the resin. After the reaction mixture was shaken for 12 hr at room temperature, the resin was washed with DMF, MeOH followed by DCM.

Step 3

25% piperidine in DMF was added to the resin swollen by DMF before the reaction and the reaction mixture was shaken at room temperature for 30 minutes. This deprotection step was repeated again and the resin was washed with DMF, MeOH followed by DCM. A solution of hydrazine acid (4 equiv.), HOBt (4 equiv.), And DIC (4 equiv.) In DMF was added to the resin and the reaction mixture was shaken at room temperature for 12 hr. The resin was washed with DMF, MeOH and DCM.

Step 4a (where hydrazine acid is MOC carbamate)

The resin obtained in step 3 was treated with formic acid (1.2 mL for each well) at room temperature for 18 hr. After removal of the resin by filtration, the filtrate was concentrated using a speed bag (SpeedVac, SAVANT) under reduced pressure to give an oily product. The product was diluted with 50% water / acetonitrile and then lyophilized.

Step 4b (here, Fmoc hydrazine acid is used to make urea through isocyanate)

25% piperidine in DMF was added to the resin swollen by DMF before the reaction and the reaction mixture was shaken at room temperature for 30 minutes. This deprotection step was repeated again and the resin was washed with DMF, MeOH and DCM. Isocyanate (5 equiv.) In DCM was added to the resin swollen by DCM before the reaction. After the reaction mixture was shaken for 12 h at room temperature, the resin was washed with DMF, MeOH followed by DCM. The resin was treated with formic acid (1.2 mL for each well) at room temperature for 18 hr. After removal of the resin by filtration, the filtrate was concentrated using a speed bag (SpeedVac, SAVANT) under reduced pressure to give an oily product. The product was diluted with 50% water / acetonitrile and lyophilized.

Step 4c (here, Fmoc-hydrazine acid is used to make urea via active carbamate)

25% piperidine in DMF was added to the resin swollen by DMF before the reaction, and the reaction mixture was shaken at room temperature for 30 min. This deprotection step was repeated again and the resin was washed with DMF, MeOH and DCM. To the resin swollen by DCM prior to the reaction, p-nitrophenyl chloroformate (5 equiv.) And diisopropyl ethylamine (5 equiv.) In DCM were added. After the reaction mixture was shaken for 12 hr at room temperature, the resin was washed with DMF, MeOH and DCM. Primary amine in DCM was added to the resin at room temperature for 12 hours, and the resin was washed with DMF, MeOH followed by DCM. After the reaction, the resin was treated with formic acid (1.2 mL for each well) at room temperature for 18 hr. After removal of the resin by filtration, the filtrate was concentrated using a speed bag (SpeedVac, SAVANT) under reduced pressure to give an oily product. The product was diluted with 50% water / acetonitrile and lyophilized.

To generate these block libraries, the core intermediate hydrazine acid was synthesized according to the procedure described in the Examples.

Dosage and Dosage

The compounds of the present invention can be administered by any means known to those skilled in the art. For example, the compounds of the present invention can be administered orally, parenterally, inhalation spray, topical, rectal administration, nasal, buccally, vaginal, or implanted reservoirs. As used herein, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intraperitoneal, intramedural, intravenous (intraventricular), intrasternal, intracranial, and intraosseous injections. ) And infusion techniques. The exact dosing protocol is altered depending on various factors including the age, body weight, general health, sex, and diet of the patient; Determination of a particular administration procedure will be routine to those skilled in the art.

Compounds of the invention may be administered by single dose, multiple discrete doses, or continuous infusion. Pump means, in particular subcutaneous pump means, are useful for continuous infusion.

Dosage levels belonging to about 0.001 mg / kg / d to about 100 mg / kg / d of the compounds of the invention are useful for the methods of the invention. In one embodiment, the dosage level is about 0.1 mg / kg / d to about 100 mg / kg / d. In another embodiment, the dosage level is about 1 mg / kg / d to about 10 mg / kg / d. Specific dosage levels for any particular patient may include the activity and possible toxicity of the specific compound employed; The age, body weight, general health, sex, and diet of the patient; Dosing time; Discharge rate; Drug combinations; Severity of the disease; And various factors including the form of administration. Typically, in vitro dose-effect results provide useful guidelines for appropriate dosages for patient administration. In addition, research is useful in animal models. Considerations for determining the appropriate dosage level are well known in the art and belong to the general practitioner's skill.

All dosage regimens known for keeping time regular and for continuation of drug delivery can be used and re-experienced as needed for effective treatment in the methods of the present invention. The therapy may comprise pretreatment and / or combination administration with additional therapeutic agent (s).

The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents for simultaneous, separate, or continuous use. Examples of additional therapeutic agents include, without limitation, compounds of the present invention; Steroids such as hydrocortisone, such as methylprednisolone; Anti-inflammatory or immunosuppressive agents such as methotrexate, azathioprine, cyclophosphamide, or cyclosporin A; Interferon-β; Antibodies such as anti-CD4 antibodies; Chemotherapeutic agents; Immunotherapy compositions; Electromagnetics radiosensitizers; And morphine. The compounds of the present invention may be independently administered in combination with one or more additional therapeutic agents (i) together in a single dosage form or (ii) in individual formulations designed so that each active drug has an optimal release rate.

The pharmaceutical composition may comprise at least one compound disclosed herein in combination with at least one cancer chemotherapeutic agent acting by a mechanism other than blocking CBP / catenin interactions. The cancer chemotherapy may be selected from the group consisting of, but not limited to, histone deacetylase (HDAC) inhibitors such as cis-platinum, retinoic acid, vorinostat (SAHA), and imatinib have.

The pharmaceutical composition may comprise at least one Her1 / Her2 inhibitor; Notch inhibitors; Hedgehog inhibitors; EGF inhibitors: and pathway-specific inhibitors such as P13K pathway inhibitors. The notch inhibitor may be a gamma secretase inhibitor, the hedgehog inhibitor may be cyclopamine, the EGF inhibitor may be Iressa, and the P13K pathway inhibitor is rapamycin (rapamycin).

Pharmaceutical composition

The present invention also provides an effective amount of (i) an effective amount of a compound of Formula I, II, or III; And (ii) it provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may comprise one or more wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, sweeteners ), And one or more additional pharmaceutically acceptable ingredients, including, without limitation, additional therapeutic agents.

The pharmaceutical compositions of the present invention may be formulated in solid or liquid form for the following: (1) For example, branches (aqueous or aqueous or non-aqueous solutions or suspensions), tablets (eg buccal) oral administration such as buccal, sublingual or targeted for systemic absorption), bolus, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, oral sprays, emulsions, and microemulsions ; (2) parenteral administration such as, for example, subcutaneous, intramuscular, eg, sterile solutions, intravenous or epidural injections, such as suspensions, or sustained release formulations; (3) topical applications such as, for example, controlled-release patches or sprays applied to creams, ointments, or skin; (4) intravaginal or rectal administration, such as, for example, pessary, cream, or foam; (5) sublingual administration; (6) ocular administration; (7) transdermal administration; Or (8) nasal administration.

The embodiments and embodiments described herein are for illustrative purposes only, and various modifications and changes may be suggested to those skilled in the art in their view, and such modifications and changes are included within the spirit and scope of the present application. It must be understood.

Example  One

Intermediate synthesis

2- Boc -Amino- Benzothiazolyl Synthesis of 4-methylamine

Step-1 (2-Boc-amino-4-methylbenzothiazole)

A solution of 2-amino-4-methylbenzothiazole (25.0 g, 152 mmol) in 456 mL of dry THF was added at 20 ° C. with Et ₃ N (42 mL, 300 mmol), (Boc) ₂ O (40.0 g, 183 mmol). , And DMAP (3.7 g, 30 mmol) and stirred at 30 ° C. for 12 hr. The solution obtained above was concentrated under vacuum, diluted with EtOAc (200 mL) and filtered through a glass filter (Celite) washed with EtOAc (200 mL). The filtrate was washed with NaHCO ₃ (saturated aqueous solution, 100 mL) and NaCl (saturated aqueous solution, 100 mL), dried over MgSO ₄ , and concentrated in vacuo. The residue was filtered through a silica gel plug (flash column chromatography) eluting with toluene: Et ₂ O (15: l to 8: 1) to give a colorless oil, 2-Boc-amino-4-methylbenzo. Thiazole (41.4 g, quant.) Was obtained. R _f = 0.4 S (toluene: Et ₂ O = 10: l); ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.75 (1H, br s), 7.61 (1H, d, J = 7.8 Hz), 7.19 (3H, m), 2.64 (3H, s), 1.47 (9H, s) .

Step-2 (2-Boc-amino-4-bromomethylbenzothiazole)

Dry CCl ₄ A solution of 2-Boc-amino-4-methylbenzothiazole (152 mmol) in 456 mL was treated with NBS (27.1 g, 152 mmol) and AIBN (3.2 g, 20 mmol) at 20 ° C. and 3.5 hr at 80 ° C. Was stirred. The mixture was treated again with NBS (7.2 g, 41 mmol) and AIBN (0.84 g, 5.1 mmol) at 20 ° C. and stirred at 80 ° C. for 11 hr. The mixture obtained above was cooled to 20 ° C. and filtered through a glass filter (Celite) washed with Et ₂ O (200 mL). The filtrate was concentrated under vacuum. The residue was filtered through a silica gel column (flash column chromatography) eluting with toluene: Et ₂ O (20: l to 10: 1) to give a yellowish oil, 2-Boc-amino-4-bromo. Methylbenzothiazole (46.7 g, 136 mmol, 90%) was obtained. R _f = 0.51 (toluene: Et ₂ O = 15: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (1H, br s), 7.72 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 7.2 Hz), 7.24 (1H, dd, J = 8.2, 7.2 Hz), 4.91 (2H, s), 1.56 (9H, s).

Step-3 (2-Boc-amino-4-azidomethylbenzothiazole)

A solution of 2-Boc-amino-4-bromomethylbenzothiazole (46.7 g, 136 mmol) in 205 mL dry DMF was treated with NaN ₃ (8.80 g, 136 mmol) at 15 ° C. and 45 min at 20 ° C. Stirred. The mixture obtained above was diluted with Et ₂ O (400 mL) and the reaction was stopped by addition of NaCl (1 g in 150 mL of H ₂ O) at 0 ° C. The solution was extracted with Et ₂ O (100 mL). The organic phase was washed twice with NaCl (2 g in 100 mL H ₂ O), dried over MgSO ₄ and concentrated in vacuo. The residue was filtered through a silica gel plug (flash column chromatography) eluting with toluene: Et ₂ O (100: 0 to 10: 1) to give a colorless oil, 2-Boc-amino-4-azido. Methylbenzothiazole (33.2 g, 109 mmol, 80%) was obtained. R _f = 0.48 (toluene: Et ₂ O = 10: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (1H, d, J = 8.2 Hz), 7.37 (1H, d, J = 7.2 Hz), 7.27 (1H, m), 4.74 (2H, s), 1.52 ( 9H, s); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 159.8, 151.9, 147.6, 132.5, 127.6, 125.8, 123.5, 121.3, 83.4, 51.4, 28.1.

Step-4 (2-Boc-amino-benzothiazolyl-4-methylamine)

A solution of 2-Boc-amino-4-azidomethylbenzothiazole (11.6 g, 38.0 mmol) in 183 mL of MeOH was treated with Pd (OH) ₂ (20% for carbon, 2.9 g) and placed under hydrogen atmosphere. And stirred at 20 ° C. for 1.5 hr. The mixture obtained above was filtered through Celite washed with MeOH: NH ₄ OH (100: 3, 100 mL) and concentrated under vacuum. The yellowish solid obtained above was triturated with toluene (35 mL) and filtered to give a colorless powder, 2-Boc-amino-benzothiazolyl-4-methylamine (6.90 g, 24.7 mmol, 65%). It was. R _f = 0.32 (CHCl ₃ : MeOH: NH ₄ OH = 100: 25: l); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (1H, d, J = 7.7 Hz), 7.25-7.15 (2H, m), 4.85 (2H, br s), 1.58 (9H, s); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 160.0, 152.8, 148.0, 134.5, 132.7, 124.4, 123.1, 120.0, 82.4, 44.3, 28.3; LC / MS [ESI < + >] (m / z) 280.2 (M + 1) ⁺ .

Benzothiazolyl Synthesis of 4-methylamine

Step-1 (4-methylbenzothiazole)

A solution of 2-amino-4-methylbenzothiazole (24.5 g, 149 mmol) in 745 mL of 1,4-dioxane was treated with isoamnitrile (40.0 mL, 300 mmol) at 20 ° C. and 0.5 at 70 ° C. Stir for hr. After the nitrogen release had subsided, the mixture was stirred at the same temperature for 1.5 hr and concentrated under vacuum. The residue was purified by silica gel column chromatography using hexane: Et ₂ O (3: 1 to 2: 1) as eluent to obtain a yellowish oil, 4-methylbenzothiazole (16.0 g, 107 mmol, 72%). Obtained. R _f = 0.45 (toluene: Et ₂ O = 10: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.98 (1H, s), 7.79 (1H, d, J = 6.8 Hz), 7.33 (2H, m), 2.80 (3H, s).

Step-2 (4-bromomethylbenzothiazole)

CCl ₄ 4-methylbenzothiazole (16.0 g, 107 mmol) solution in 535 mL was treated with NBS (19.0 g, 107 mmol) and AIBN (2.28 g, 13.9 mmol) at 20 ° C. and stirred at 70 ° C. for 2.5 hr. . The mixture obtained above was filtered through Celite washed with Et ₂ O (150 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography using toluene: Et ₂ O (50: 3 to 50: 5) as eluent to give a yellowish solid, 4-bromomethylbenzothiazole (20.4 g, 89.9 mmol, 84%). ) Was obtained. R _f = 0.61 (toluene: Et ₂ O = 10: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (1H, s), 7.90 (1H, d, J = 7.5 Hz), 7.55 (1H, d, J = 7.5 Hz), 7.41 (1H, t, J = 7.5 Hz), 5.08 (2H, s); ¹³ C NMR (99.5 MHz, CDCl 3) δ 154.1, 151.4, 134.3, 132.6, 127.0, 125.6, 122.3, 29.5.

Step-3 (4-azidomethylbenzothiazole)

A solution of 4-bromomethylbenzothiazole (20.4 g, 89.9 mmol) in 272 mL of dry DMF was treated with NaN ₃ (7.00 g, 108 mmol) at 20 ° C. and stirred at the same temperature for 5 min. Stop the reaction by the addition of (5 g of H ₂ O 150 mL) and the mixture obtained above at 0 ℃ NaCl was diluted with Et ₂ O (200 mL), extracted with _{Et 2 O (200 mL X 6} ) . The organic phase was washed twice with NaCl (2 g in 100 mL H ₂ O) and brine (100 mL). The solution obtained above was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography using toluene: Et ₂ O (50: 3 to 50: 5) as eluent to obtain a colorless oil, 4-azidomethylbenzothiazole (15.5 g, 81.5 mmol, 91%). It was. R _f = 0.48 (toluene: Et ₂ O = 10: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.03 (1H, s), 7.95 (1H, d, J = 7.7 Hz), 7.49 (2H, m), 5.01 (2H, s); ¹³ C NMR (99.5 MHz, CDCl 3) δ 154.2, 151.7, 134.3, 130.6, 126.0, 125.7, 122.1, 51.6.

Step-4 (benzothiazole-4-methylamine)

To a solution of 4-azidomethylbenzothiazole (15.4 g, 81.0 mmol) in 243 mL of MeOH was added Pd (OH) ₂ (20% for carbon, 3.1 g), followed by hydrogenolysis at 20 ° C. I was. After 1.5 hr, additionally Pd (OH) ₂ (20% relative to carbon, 0.87 g) was added and hydrocracked. After 1.5 hr, additionally Pd (OH) ₂ (20% for carbon, 1.27 g) was added and hydrocracked for 1 hr. The mixture obtained above was put back with N ₂ and filtered through celite washed with MeOH: NH ₄ OH (25: 1, 260 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography using CHCl ₃ : MeOH: NH ₄ OH (100: 0: 0 to 20: 5: 1) as an eluent and triturated with toluene to give a white solid, 4-aminomethylbenzothiazole. (10.5 g, 63.9 mmol, 79%) was obtained. R _f = 0.49 (CHCl ₃ : MeOH: NH ₄ OH = 100: 25: 1); ¹ H NMR (400 MHz, CD ₃ OD) δ 9.23 (1H, s), 7.97 (1H, d, J = 7.7 Hz), 7.46 (2H, m), 4.30 (2H, s); ¹³ C NMR (99.5 MHz, CD ₃ OD) δ 184.2, 180.1, 165.3, 163.5, 154.9, 154.1, 150.1, 72.0; LC / MS [ESI < + >] (m / z) 165.4 (M + 1) ⁺ .

4-benzyl-3- Boc -2- Methyl Semicarbazidyl Acetic Acid  synthesis

Step-1 (4-benzyl-2-methylsemicabazide)

CHCl ₃ A solution of benzyl isocyanate (1.85 mL, 15.0 mmol) in 7.5 mL was treated with methyl hydrazine (795 μL, 15.0 mmol) at 0 ° C. and stirred for 2 hr at the same temperature. The mixture obtained above was dissolved in 1N HCl (200 mL) and the solution was washed with CHCl ₃ (50 mL X 3). The aqueous phase was adjusted to pH 12 with 2 M NaOHaq and extracted with CHCl ₃ (100 mL × 3). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was recrystallized in hexane-CHCl ₃ to give colorless crystals (1.7 g, 9.5 mmol, 63%). R _f = 0.44 (CHCl ₃ : MeOH = 9: 1); ¹ H NMR (400 MHz, DMSO-d 6) δ 7.28-7.19 (5H, m), 4.47 (2H, s), 4.20 (2H, d, J = 6.3 Hz), 2.96 (3H, s); ¹³ C NMR (99.5 MHz, DMSO-d 6) δ 159.3, 141.1, 128.1, 127.1, 126.5, 43.1, 37.8; LC / MS [ESI < + >] (m / z) 180.3 (M + 1) ^+.

Step-2 (Ethyl 4-benzyl-2-methylsemicabazidyl acetate)

To a solution of 4-benzyl-2-methylsemicabazide (5.24 g, 29.2 mmol) in toluene (58 mL) was added DIPEA (7.63 mL, 43.8 mmol) and ethyl bromoacetate (4.86 mL, 43.8 mmol), 85 Stir at rt for 24 hr. The reaction mixture was allowed to cool to rt and then diluted with EtOAc (100 mL). The mixture was washed with H ₂ O (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude was purified by silica gel (250 g) using Hex: EtOAc (1: 1 to 1: 9) as eluent to give a pale yellow oil (5.75 g, 21.7 mmol, 74%). R _f = 0.36 (Hex: EtOAc = l: 3); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.21 (5H, m), 6.88 (1H, br s), 4.40 (2H, d, J = 5.8 Hz), 4.18 (2H, q, J = 7.2 Hz) , 3.69 (1H, broad, J = 4.8 Hz), 3.58 (2H, d, J = 4.8 Hz), 3.08 (3H, s), 1.26 (3H, t, J = 7.2 Hz); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 170.8, 159.3, 139.9, 128.6, 127.6, 127.1, 61.4, 50.1, 44.4, 33.1, 14.2; LC / MS [ESI < + >] (m / z) 266.3 (M + 1) ⁺ .

Step-3 (Ethyl 4-benzyl-3-Boc-2-methylsemicabazidilacetate)

DIPEA (7.5 mL, 43 mmol), DMAP (1.1 g, 8.6 mmol), in a solution of ethyl 4-benzyl-2-methylsemicabazidil acetate (5.70 g, 21.5 mmol) in CH ₂ Cl ₂ (43 mL), and ( Boc) ₂ 0 (9.4 g, 43 mmol) was added and stirred at rt for 1 hr. The reaction mixture was concentrated and pale yellow oil product (2.58 g, 7.06 mmol, 33%) by column chromatography with SiO ₂ (250 g) using Hex: EtOAc (7: 1 to 1: 2) as eluent. ) And the starting material (2.80 g, 10.6 mmol, 49%) was recovered. R _f = 0.76 (Hex: EtOAc = 1: 3); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (1H, br s), 7.33-7.20 (5H, m), 4.59-4.46 (2H, m), 4.27-4.19 (4H, m), 3.72 (1H, br d, J = 17 Hz), 3.03 (3H, br s), 1.39 (9H, s), 1.26 (3H, t, J = 7.2 Hz); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 170.7, 158.3, 139.8, 128.3, 127.6, 126.9, 82.7, 62.0, 51.6, 44.3, 34.4, 28.0, 14.1; LC / MS [ESI < + >] (m / z) 366.3 (M + 1) ⁺ .

Step-4 (4-benzyl-3-Boc-2-methylsemicabazidylacetic acid)

To a solution of ethyl 4-benzyl-3-Boc-2-methylsemicabazidylacetate (2.30 g, 6.29 mmol) in THF / MeOH / H ₂ O (2/3/1, 24 mL) at 0 ° C. LiOH H ₂ O ( 528 mg, 12.6 mmol) was added. After stirring for lhr at room temperature, the reaction mixture was diluted with EtOAc (40 mL) at 0 ° C. The mixture was acidified with 1N HCl and extracted with EtOAc. The combined extracts were washed with H ₂ O (30 mL) and brine (30 mL), dried over Na ₂ SO ₄ , Et ₃ N (2 mL) was added, filtered and concentrated. SiO ₂ using CHCl ₃ : MeOH (= 100: 0 to 85:15) as an eluent Chromatography gave a pale yellow sticky oil, 4-benzyl-3-Boc-2-methylsemicabazidylacetic acid Et ₃ N salt (1.99 g, 4.56 mmol, 72%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (1H, br s), 7.32-7.18 (5H, m), 4.58-4.22 (3H, m), 3.71-3.57 (1H, m), 3.08 and 3.01 (3H , br s), 2.82 (2.4H, q, J = 7.3 Hz, Et ₃ N), 1.40 (9H, br s), 1.08 (3.6H, t, J = 7.3 Hz, Et ₃ N); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 174.2, 159.2, 154.1, 140.1, 128.2, 127.4, 12.7, 81.8, 52.2, 45.1 (Et ₃ N), 44.1, 34.5, 28.1, 8.3 (Et ₃ N); LC / MS [ESI < + >] (m / z) 338.3 (M + 1) ⁺ .

4-benzyl-3- Boc -2- Of allyl semicarbazyl acetic acid  synthesis

Step-1 (4-benzyl-2-allyl semicarbazide)

CHCl ₃ To a solution of allyl hydrazine (1.55 mL, 15.0 mmol) in 7.5 mL was slowly added benzyl isocyanate (1.85 mL, 15.0 mmol) at 0 ° C. and stirred at the same temperature for 2 hr. The mixture obtained above was dissolved in 1N HCl (200 mL) and the solution was washed with CHCl ₃ (50 mL X 3). The aqueous phase was adjusted to pH 12 with 2 M NaOHa and extracted with CHCI ₃ (100 mL X 3). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was taken up in hexane-CHCl ₃ Recrystallization gave colorless crystals (2.20 g, 10.7 mmol, 70%). R _f = 0.50 (CHCl ₃ : MeOH = 9: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.23 (5H, m), 6.77 (1H, br s), 5.77 (1H, ddt, J = 16.9, 10.1, 6.3 Hz), 5.28 (1H, d, J = 10.1 Hz), 5.22 (1H, dd, J = 16.9, 1.5 Hz), 4.42 (2H, d, J = 6.3 Hz), 4.14 (2H, d, J = 6.3 Hz), 3.47 (2H, s); ¹³ C NMR (99.5 MHz, CDCl ₃ ) 5159.0, 139.9, 132.7, 128.6, 127.6, 127.2, 119.2, 52.8, 44.3; LC / MS [ESI < + >] (m / z) 206.3 (M + 1) ⁺ .

Step-2 (Ethyl 4-benzyl-2-allyl semicarbazidyl acetate)

To a solution of 4-benzyl-2-allyl semicarbazide (8.60 g, 41.9 mmol) in toluene (50 mL) was added DIPEA (14.6 mL, 83.8 mmol) and ethyl bromoacetate (8.1 mL, 73 mmol), 95 Stir at 39 ° C. for 39 hr. The reaction mixture was allowed to cool to rt and then diluted with EtOAc (150 mL). The mixture was washed with H ₂ O (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by column chromatography on silica gel (250 g) using Hex: EtOAc (2: 1 to 1: 1) as eluent to give a pale yellow oil (7.60 g, 26.1 mmol, 62%). R f = 0.30 (Hex: EtOAc = 2: 3); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.23 (5H, m), 7.02 (1H, br, s), 5.78 (1H, ddt, J = 17.4, 10.1, 6.3 Hz), 5.25 (2H, m) , 4.42 (2H, d, J = 5.8 Hz), 4.16 (3H, q and br m, J = 7.2 Hz), 3.98 (1H, t, J = 4.8 Hz), 3.55 (2H, d, J = 4.8 Hz ), 1.25 (3H, t, J = 7.2 Hz); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 170.5, 158.9, 139.8, 132.5, 128.5, 127.6, 127.1, 119.2, 61.3, 50.0, 46.7, 44.3, 14.1; LC / MS [ESI < + >] (m / z) 292.3 (M + 1) ⁺ .

Step-3 (Ethyl 4-benzyl-3-Boc-2-allyl semicarbazidyl acetate)

DIPEA (8.5 mL, 49 mmol), DMAP (1.19 g, 9.76 mmol) and (Boc) in a solution of ethyl 4-benzyl-2-allyl semicarbazidil acetate (7.10 g, 24.4 mmol) in CH ₂ Cl ₂ (50 mL) ) ₂ 0 (10.6 g, 48.8 mmol) was added. After the mixture was stirred at room temperature for 3.5 hr, additionally DIPEA (2.12 mL, 12.2 mmol) and (Boc) ₂ O (2.66 g, 12.2 mmol) were added. The reaction mixture was stirred for an additional 6 hr, the mixture was diluted with CH ₂ Cl ₂ (100 mL) and then saturated NaHCO ₃ (50 mL) was added at 0 ° C. The separated aqueous phase was extracted with CH ₂ Cl ₂ (100 mL X 2). The combined organic phases were washed with H ₂ O (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by column chromatography on SiO ₂ (300 g) using Hex: EtOAc (7: 1 to 1: 1) as eluent to give the pale yellow oil (6.61 g, 16.9 mmol, 69%) product. It was. R f = 0.57 (Hex: EtOAc = 1: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (1H, br s), 7.34-7.21 (5H, br m), 5.88 (1H, br m), 5.20 (2H, br m), 4.62-4.46 (3H, m), 4.37-4.13 (3H, m), 3.92-3.65 (2H, m), 1.48 and 1.38 (9H, s), 1.26 (3H, t, J = 7.2 Hz); ¹³ C NMR (99.5 MHz, CDCl 3) δ 170.8, 157.8, 154.1, 139.8, 128.4, 127.6, 127.0, 119.6, 82.7, 62.0, 51.2, 44.3, 30.9, 28.0, 14.1; LC / MS [ESI < + >] (m / z) 392.4 (M + 1) ⁺ .

Step-4 (4-benzyl-3-Boc-2-allyl semicarbazyl acetic acid)

_{THF / MeOH / H 2 O (} 2/3/1, 25 mL) of ethyl 4-benzyl -3-Boc-2- allyl semi kabaji pyridyl acetate (3.20 g, 8.17 mmol) LiOH · H 2 0 ℃ eseo To a solution of O (685 mg, 16.3 mmol) was added. After stirring for 40 min at room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ (50 mL) at 0 ° C. The mixture was acidified with 1N HCl and extracted with CH ₂ Cl ₂ . The mixed extract was washed with H ₂ O (30 mL) and brine (30 mL), dried over Na ₂ SO ₄ , Et ₃ N (3 mL) was added, filtered and concentrated. The crude was used as an eluent as an eluate by CH _{2 3} : MeOH (100: 0 to 85:15) in SiO ₂ column chromatography to give an orange oily sticky oil 4-benzyl-3-Boc-2-allyl semicarbazidyl Acetic acid Et ₃ N salt (3.66 g, 7.87 mmol, 96%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ , rotamer) δ 9.44 and 9.34 (1H, br s), 7.35-7.18 (5H, m), 5.91 (1H, m), 5.17 (2H, m), 4.58 and 4.87 (2H , dd, J = 15.5, 6.3 and 14.5, 5.8 Hz), 4.39-4.23 (2H, m), 3.89 and 3.80 (1H, dd, J = 14.0, 8.2 and 14.5, 8.2 Hz), 3.58 and 3.52 (1H, d, J = 17.4 and 16.9 Hz), 2.81 (5H, q, J = 7.2 Hz, Et3N), 1.44 and 1.42 (9H, s), 1.11 (7.5H, t, J = 7.2 Hz, Et 3 N); ¹³ C NMR (99.5 MHz, CDCl ₃ ) δ 158.9, 154.3, 153.6, 140.6, 134.2, 128.1, 127.4, 126.5, 118.8, 81.1, 55.6, 51.4, 44.9 (Et ₃ N), 44.2, 28.2, 8.3 (Et ₃ N); LC / MS [ESI < + >] (m / z) 364.3 (M + 1) ⁺ .

compound No Synthesis of .61

Step-1

In a 200 mL round bottom flask was added hydroxy-functionalized resin (5.0 g, 0.68 mmol / g, NovAblochem). To a mixture of this resin and PPTS (1.7 g, 6.8 mmol) in 1,2-dichloromethane (51 mL) was added bromoacetaldehyde diethylacetal (4.2 mL, 27 mmol) at room temperature. After stirring under reflux for 4.0 hr, the mixture is filtered and the resin is filtered with DMF (50 mL X 3), DMSO (50 mL X 3), 1,4-dioxane (50 mL X 3), CH ₂ Cl Washed with ₂ (50 mL X 3), MeOH (50 mL X 3), Et ₂ O (50 mL X 3). The resin was dried overnight under reduced pressure to afford the desired bromoacetal resin (5.5 g).

Step-2

Bromoacetal resin (1.0 g, 0.9 mmol / g) was placed in a 30 mL round bottom flask. The resin was swollen with DMF (9.0 mL X 5 min X 1) and treated with a solution of 1-naphthylmethylamine (1.4 g, 9.0 mmol) in DMSO (9.0 mL) at 70 ° C. After stirring for 12 hr, the resin was filtered and rinsed with DMSO (9.0 mL X 5 min X 3). The resin was washed with DMF (5.0 mL X 5 min X 3) and CH ₂ Cl ₂ (5.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin (1.18 g).

Step-3

Naphthylmethylamino resin (1.18 g, 0.84 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen with DMF (9.0 mL X 5 min X 1), at room temperature DMF (9.0 mL), Fmoc-Tyr (t-Bu) -OH (620 mg, 1.35 mrnol), DIPEA (470 μL, 2.70 mmol) ), And HATU (513 mg, 1.35 mmol). After shaking for 12 hr, the same procedure was repeated if the Kaiser test was positive. The mixture was filtered and the resin was washed with DMF (10.0 mL X 5 min X 3) and CH ₂ Cl ₂ (10.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin (1.50 g).

Step-4

The l-naphthylmethylamino-Fmoc-Tyr (tBu) resin (1.50 g, 0.61 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen in DMF (10.0 mL) and all the DMF was sucked up. The resin was treated with 20 v / v% piperidine / DMF (10.0 mL) at room temperature. After shaking for 1.0 hr, the mixture was filtered and the resin was washed with DMF (10 mL X 5 min X 3) and CH ₂ Cl ₂ (10 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin (1.48 g).

Step-5

The amino resin (300 mg, 0.71 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen in DMF (3.0 mL) and all the DMF was sucked up. 0.3 M storage of 4-benzyl-3-Boc-2-methylsemicabazidylacetic acid (2.5 mL, 0.75 mmol), DIPEA (260 μL, 1.49 mmol), and HATU (284 mg, 0.75 mmol) at room temperature in the resin CH ₂ Cl ₂ solution was added. After shaking for 12 hr, the mixture was filtered and the resin was washed with DMF (5.0 mL X 5 min X 3) and CH ₂ Cl ₂ (5.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin.

Step-6

The resin (115 mg, 0.58 mmol / g) was placed in a 5.0 mL plastic disposable syringe. After addition of 99% HCO ₂ H (1.0 mL), the mixture was shaken for 12 hr at room temperature and the solution collected by filtration. The resin was washed with 99% HCO ₂ H (1.5 mL X 5 min X 2). The mixed HCO ₂ H solution was concentrated and silica gel column chromatography gave Compound No. 61 (7.1 mg, 19% from bromoacetal resin). R f = 0.63 (CHCl ₃ : MeOH = 9: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (1H, d, J = 8.2 Hz), 7.89 (1H, m), 7.84 (1H, d, J = 8.2 Hz), 7.56 (2H, m), 7.38 ( 1H, dd, J = 8.2, 7.2 Hz), 7.20 (3H, m), 7.12 (1H, d, J = 6.8 Hz), 7.05 (2H, dd, J = 7.7, 2.9 Hz), 7.02 (2H, d , J = 8.2 Hz), 6.88 (0.5H, br s), 6.71 (2H, d, J = 8.2 Hz), 6.05 (1H, t, J = 5.8 Hz), 5.06 (2H, ABq, J = 14.5 Hz ), 4.80 (1H, dd, J = 5.8, 2.5 Hz), 4.23 (2H, ABX, J = 14.5, 5.8 Hz), 3.67-3.44 (4H, m), 3.21 (1H, dd, J = 14.0, 5.8 Hz), 3.12 (1H, doublet of doublets, J = 11.0, 3.9 Hz), 2.86 (1H.dd. J = 11.0, 9.1 Hz), 2.59 (3H, s); LC / MS [ESI < + >] (m / z) 564.4 (M + 1) ⁺ .

compound No Synthesis of .71

Step-1

The amino resin (100 mg, 0.71 mmol / g) was placed in a 5 mL plastic disposable syringe. The resin was swollen in DMF (1.0 mL) and all the DMF was sucked up. 0.3 M storage of 4-benzyl-3-Boc-2-allylsemicarbazidylacetic acid (830 μL, 0.25 mmol), DIPEA (87 μL, 0.50 mmol), and HATU (95 mg, 0.25 mmol) at room temperature in the resin CH ₂ Cl ₂ solution was added. After shaking for 12 hr, the mixture was filtered and the resin was washed with DMF (1.0 mL X 5 min X 3) and CH ₂ Cl ₂ (1.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin.

Step-2

The resin (100 mg, 0.57 mmol / g) was placed in a 5.0 mL plastic disposable syringe. After addition of 99% HCO ₂ H (1.0 mL), the mixture was shaken for 12 hr at room temperature and the solution collected by filtration. The resin was washed with 99% HCO ₂ H (1.5 mL X 5 min X 2). The mixed HCO ₂ H solution was concentrated and silica gel column chromatography gave Compound No. 71 (11 mg, 26% from bromoacetal resin). Rf = 0.63 (CHCl ₃ : MeOH = 9: 1).

Similar synthesis was performed to obtain compound 1-1200 shown in FIGS. 1-6.

compound No Synthesis of .1273

Step-1

Bromoacetal resin (1.0 g, 0.9 mmol / g) was placed in a 30 mL round bottom flask. The resin was swollen with DMF (9.0 mL X 5 min X 1) and 2-tert-butoxycarbonylaminobenzothiazole-4-methylamine (2.5 g, 9.0 mmol) in DMSO (9.0 mL) at 70 ° C. Treated with 1.0 M suspension. After stirring for 12 hr, the resin was filtered and rinsed with DMSO (9.0 mL X 5 min X 3). The resin was washed with DMF (5.0 mL X 5 min X 3) and CH ₂ Cl ₂ (5.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin (1.16 g). .

Step-2

2-tert-butoxycarbonylaminobenzothiazole-4-methylamino resin (1.16 g, 0.76 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen with DMF (9.0 mL X 5 min X 1), DMF (9.0 mL), Fmoc-Tyr (t-Bu) -OH (620 mg, 1.35 mmol), DIPEA (470 μL, 2.70 mmol) at room temperature ), And HATU (513 mg, 1.35 mmol). After shaking for 12 hr, the same procedure was repeated if the Kaiser test was positive. The mixture was filtered and the resin was washed with DMF (10.0 mL X 5 min X 3) and CH ₂ Cl ₂ (10.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin (1.76 g).

Step-3

2-tert-butoxycarbonylbenzothiazole-4-methylamino-Fmoc-Tyr (tBu) resin (1.76 g, 0.57 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen in DMF (1.0 mL) and all the DMF was sucked up. The resin was treated with 20 v / v% piperidine / DMF (10.0 mL) at room temperature. After shaking for 1.0 hr, the mixture was filtered and the resin was washed with DMF (10 mL X 5 min X 3) and CH ₂ Cl ₂ (10 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin (1.42 g).

Step-4

The amino resin (350 mg, 0.65 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen in DMF (3.0 mL) and all the DMF was sucked up. 0.3 M storage of 4-benzyl-3-Boc-2-methylsemicabazidylacetic acid (2.7 mL, 0.80 mmol), DIPEA (277 μL, 1.59 mmol), and HATU (302 mg, 0.80 mmol) at room temperature in the resin. CH ₂ Cl ₂ solution was added. After shaking for 12 hr, the mixture was filtered and the resin was washed with DMF (5.0 mL X 5 min X 3) and CH ₂ Cl ₂ (5.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin.

Step-5

The resin (350 mg, 0.65 mmol / g) was placed in a 20 mL plastic disposable syringe. After addition of 99% HCO ₂ H (4.0 mL), the mixture was shaken for 12 hr at room temperature, and the solution was collected by a filter. The resin was washed with 99% HCO ₂ H (4.0 mL X 5 min X 2). The mixed HCO ₂ H solution was concentrated and silica gel column chromatography gave Compound No. 1273 (9.1 mg, 6.8% from bromoacetal resin). R _f = 0.47 (CHCl ₃ : Me0H = 9: l).

compound No Synthesis of .1285

Step-1

The amino resin (350 mg, 0.65 mmol / g) was placed in a 20 mL plastic disposable syringe. The resin was swollen in DMF (3.0 mL) and all the DMF was sucked up. 0.3 M storage of 4-benzyl-3-Boc-2-allylsemicarbazidylacetic acid (2.7 mL, 0.80 mmol), DIPEA (277 μL, 1.59 mmol), and HATU (302 mg, 0.80 mmol) at room temperature in the resin. CH ₂ Cl ₂ solution was added. After shaking for 12 hr, the mixture was filtered and the resin was washed with DMF (5.0 mL X 5 min X 3) and CH ₂ Cl ₂ (5.0 mL X 5 min X 3). The resin was dried under reduced pressure to give the desired resin.

Step-2

The resin (350 mg, 0.53 mmol / g) was placed in a 20 mL plastic disposable syringe. After addition of 99% HCO ₂ H (4.0 mL), the mixture was shaken for 12 hr at room temperature and the solution collected by filtration. The resin was washed with 99% HCO ₂ H (4.0 mL X 5 min X 2). The mixed HCO ₂ H solution was concentrated and purified by silica gel column chromatography. 1285 (18 mg, 13% from bromoacetal resin) was obtained. R _f = 0.52 (CHCl ₃ : Me0H = 9: l).

As shown in FIGS. 7-11, similar synthesis was performed to obtain compounds 1201-2200.

compound No . Synthesis of 2201

Compound No. in THF (500 mL). Et ₃ N (13.4 μL, 0.096 mmol) and POCl ₃ (14.9 μL, 0.160 mmol) were added to a 61 (18 mg, 0.032 mmol) cooled (0 ° C.) solution and the mixture was removed when SM disappeared on TLC. Stir until (4 hr). The mixture was diluted with H ₂ O (1 mL) and NaHCO ₃ was added to pH 8 at 0 ° C. After stirring overnight, the mixture was acidified to pH 3 with 1N HCl and extracted with CHCl ₃ (5 mL × 3). The mixed extract was dried over Na ₂ SO ₄ , filtered and concentrated to give a pale yellow powder Compound No. 2201 (17.1 mg, 83%) was obtained. TLC: R _f = 0.45 silica gel F254,

CHCl ₃ : MeOH: EtOH: H ₂ O: AcOH: nBuOH = 100: 40: 10: 10: 8: 5; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (1H, d, J = 7.7 Hz), 7.83 (1H, m), 7.77 (1H, d, J = 8.2 Hz), 7.51 (2H, m), 7.35 ( 1H, t, J = 7.3 Hz, 7.24-6.93 (1OH, m), 6.07 (1H, br s), 5.86 (3H, br s), 5.34 (1H, br d, J = 15.0 Hz), 4.76 ( 2H, m), 4.11 (2H, br ABX, J = 15.5, 5.3 Hz), 3.62 (2H, m), 3.47 and 3.31 (2H, br ABq, J = 15.0 Hz), 3.22 (2H, br m), 3.02 (1H, broad singlet), 2.77 (1H, broaden, J = 10.6 Hz), 2.56 (3H, broading); ³¹ P NMR (160.26 MHz, CDCl ₃ ) δ −3.57.

compound No . Synthesis of 2202

Compound No. in THF (1.0 mL). Et ₃ N (14.9 μL, 0.107 mmol) and POCl ₃ (16.6 μL, 0.178 mmol) were added to a cooled (0 ° C.) solution of 71 (21 mg, 0.036 mmol) and the mixture was removed when SM disappeared on TLC. Stir until (4 hr). The mixture was diluted with H ₂ O (1 mL) and NaHCO ₃ was added to pH 8 at 0 ° C. After stirring overnight, the mixture was acidified to pH 3 with 1N HCl and extracted with CHCl ₃ (5 mL × 3). The mixed extract was dried over Na ₂ SO ₄ , filtered and concentrated to give a pale yellow powder Compound No. 2202 (21.0 mg, 88%) was obtained. TLC: R _f = 0.53 silica gel F254,

CHCl ₃ : MeOH: EtOH: H ₂ O: AcOH: nBuOH = 100: 40: 10: 10: 8: 5.

 As shown in FIG. 27, similar synthesis was performed to obtain compound 2203-2217. Diastereomers and enantiomers of Compound 2203-2217 were obtained, which are shown in FIG. 12.

Table 2 below shows the molecular weight (M. W.) and mass for compound 1-2217.

Example  3

For cancer cell lines ICG -001 and Of imatinib  effect

For this example, human ovarian sarcoma cell MES-SA and the corresponding doxorubicin-resistant cell line MES-SA / Dx5 (Hua J et al Gynecologic Oncol. 2005) and the CML induced cell line K562 and alloimatinib mesylate resistant K562 cells (Dai) Y et al JBC 279, 34227, 2004). Both resistant (R) cell lines, as assessed by immunoblotting (FIG. 14A) and immunofluorescence microscopy (FIG. 14B), have dramatic levels of cytoplasmic and nuclear β-catenin compared to their drug sensitive counterparts. Indicated. The increased nuclear β-catenin, as assessed by the TOPFLASH reporter, reflected a dramatically increased TCF / β-catenin transcriptional activity, and it was completely using dominant negative TCF4 constructs. Could be blocked (FIG. 14C).

To confirm that activation of the Wnt / β-catenin pathway is important for MDR- 1 expression activation in MES-SA cells, the following experiments were performed. MES-SA cells were transfected with a topflash or popflash reporter and treated with medium alone or with addition of Wnt3a or Wnt5a. The "standard" Wnt3a but not the "non-canonical" Wnt5a increased luciferase activity by -4 fold, and the increased activity was completely blocked by cotransfection of the dnTCF4 construct ( 15A). Similarly, a 2-fold increase in MDR- 1 / luciferase activity by Wnt3a treatment was observed. In addition, this activation was completely inhibited by the transfection of the dnTCF4 construct. Wnt5a regulatory media did not show increased expression of the MDR-1 / luciferase reporter construct (FIG. 15B).

To identify the importance of nuclear β-catenin's role in inducing MDR- 1 expression, an isogenic HCT-116 cell line was used (Waldmann 2002). Wild-type HCT-116 cells demonstrated the highest MDR- 1 expression as assessed by both MDR -1 / luciferase activity and real-time RT-PCR (FIG. 15C, D). Wild type alleles of β-catenin are eliminated, oncogenic alleles are maintained, and Hβl8 (ko / *) cells with slightly lower levels of nuclear β-catenin are slightly reduced MDR- 1 Reduction in luciferase activity and MDR- 1 messages (FIG. 15C, D). Hβ92 (wt / ko) cells in which wild-type alleles were maintained and tumorigenic alleles were removed showed a much more dramatic decrease in MDR- 1 / luciferase activity and messages (FIG. 15C, D).

TCF / β-catenin recruitment from MES-SA and MES-SA / Dx5 cells to the MDR- 1 promoter was investigated. As assessed by the levels of acetylated histone H3 in the promoter, MDR- 1 is actively transcribed and In expressed MES-SA / Dx5 cells, there was a clear recruitment of TCF4 and β-catenin into the promoter and not in the parental MES-SA cell line (FIG. 15E).

To investigate the utility of other coactivators for transcriptional regulation of MDR- 1 genes in MES-SA cells, the chemogenomic tool ICG-001 was used (Emami et al. 2004). ICG-001 reduced MDR- 1 / luciferase activity in MES-SA / Dx5 cells with an IC ₅₀ of ˜16 μM (FIG. 16A). In addition, the levels of MDR- 1 protein expression in MES-SA / Dx5 cells were significantly reduced by ICG-001, as assessed by immunofluorescence (FIG. 16B) and immunoblotting (FIG. 16C) in a dose dependent manner. This effect was reflected in the message level as assessed by real-time RT-PCR in MES-SA / Dx5 cells (FIG. 16D) and imatinib mesylate resistant K562 cells (FIG. 16E).

MDR- 1 transcriptional regulation was also investigated in pseudogenic HCT116 cell lines. Throughout this pseudogenic HCT116 cell line, the co-fection of point mutants that structurally transfer β-catenin and CBP increases MDR- 1 / luciferase expression (FIG. 17A), while Transfection of point mutant β-catenin alone increased luciferase activity in Hβ92 (wt / ko) cells compared to non-transfection controls (FIG. 17A), and the Hβ92 (wt / ko) The cells have a very limited amount of nuclear β-catenin. Transfection of p300 reduced MDR- 1 / luciferase activity below the level of the control in all three cell lines (FIG. 17A). ICG-001 dose-dependently reduced MDR- 1 / luciferase activity in wild-type HCT-116 and Hβl8 (ko / *) cell lines, while in Hβ92 (wt / ko) cells it was essentially lower than basal levels. Abnormal reduction was not observed (FIG. 17B) and is consistent with the lack of β-catenin / CBP induced transcription in these cells (H Ma et al Oncogene 2005).

ChIP analysis in MES-SA / Dx5 cells demonstrated that in untreated cells there was a significant occupancy of the MDR- 1 promoter by CBP, which was blocked in a dose dependent manner by ICG-001 (FIG. 17C). Conversely, in the absence of ICG-001, there was minimal occupancy of the MDR- 1 promoter by p300, but the occupancy increased with treatment of 25 μM ICG-001 (FIG. 17C). A similar ICG-001 induced the recruitment of p300 to the previously observed survivin promoter, which was associated with recruitment of proteins involved in transcriptional inhibition (ie HDAC6 and PML) (H Ma et al. Oncogene 2005). The proposed unbinding mechanism suppresses the recruitment of transcriptional apparatus to the MDR-1 promoter by p300.

The mRNA levels of endogenous CBP coactivators in MES-SA / Dx5 cells were also significantly increased as compared to MES-SA cells, but the p300 level message remained essentially equivalent (FIG. 18A). As in immunoblotting in MES-SA / Dx5 compared to MES-SA parental lines, immunofluorescence also demonstrated a substantial increase in CBP (FIG. 18B); p300 protein levels remained essentially equivalent (FIG. 18C).

Combined immunoprecipitation of CBP or p300 showed strong association of CBP and β-catenin in MES-SA / Dx5 cells that were not present in MES-SA cells (FIG. 18D), while p300 and β-catenin The binding of was virtually undetectable in either cell line. Finally, coactivator specific siRNA was used to knock down either CBP or p300 in MES-SA / Dx5 cells (H Ma Oncogene 2005). MDR- 1 messages were specifically reduced by treatment with siRNA against CBP compared to siRNA control treated cells, whereas p300 siRNA increased MDR- 1 message levels compared to control (FIG. 18E). In culture, MES-SA / Dx5 and K562 imatinib resistant cells grew at a somewhat faster rate than the corresponding sensitive cell lines (FIG. 19A, B). Consistent with previous data (Emami et al PNAS 2004, H. Ma et al Oncogene 2005, and J Teo et al 2005), enhanced β-catenin / CBP induced transcription was both resistant cell lines compared to sensitive counterparts. Were reflected in both message (FIG. 19C, D) and protein levels (FIG. 19E, F) for both sorbbin and cyclin Dl.

To further investigate the "cancer stem cell" properties of these resistant cell lines, the expression of many markers related to the pluripotency and survival of stem cells was measured. Real-time RT-PCR demonstrated increased expression of Oct4 , hTert , Bmi- 1 and ABCG-2 in MES-SA / DX5 and Imatinib resistant K562 cells compared to their sensitive counterparts (FIG. 20A). In addition, protein levels were increased for both Oct4 and stem cell surface marker CD 133 in both resistant cell lines (FIG. 20B).

Although modern chemotherapy kills the majority of cells in tumors, it is believed that resistant "cancer stem cells" are highly associated with disease recurrence. MDR transporters are believed to play a significant role in protecting cancer stem cells from chemotherapy (Dean et al, Nat. Rev. Cancer 5, 275, 2005). To further study this phenomenon, a series of experiments were performed. Drug Resistant MES-SA / Dx5 and K562 Imatinib resistant cells were treated with doxorubicin +/- ICG-001 or imatinib mesylate +/− 001. As can be seen in FIG. 21A, ICG-001 in combination with each chemotherapy agent was significantly more effective than chemotherapeutic agents alone or ICG-001 alone in reducing cell proliferation / viability. The addition of ICG-001 to MES-SA / Dx5 cells treated with either 1 mg / ml or 5 mg / ml of doxorubicin significantly increased caspase 3/7 activation.

Example  4

Chronic bone marrow (Sex) leukemia ( CML For) ICG -001 Effect

Although significant clinical success has been achieved in CML patients using imatinib to date, in late-stage disease, the response is often transient and patients invariably undergo disease progression (MeIo J Hematology , 2003). This is the result of the appearance of leukemia drug resistant clones associated with increased nuclear β-catenin levels (Weissman NEJM 2003), which are evidence of increased TCF / β-catenin transcription. The efficacy of ICG-001 alone or in combination with imatinib mesylate was investigated at various stages of development from normal CD34 + blast cells (mostly early stem / progenerators) and bone marrow of CML patients. CD34 + CML blast compared to CD34- cells, showed the β- catenin, ABCB1, htert, the facility empty / strain Λ Ex3, and a significantly higher expression of BMI -1, these results indicate the structural activity of the Wnt / -catenin signal , Confirms the increase in "stem / progenerator-like" characteristics of this CD34 + CML blast cell population (FIG. 21C) (Jamieson et al, 2004).

  ICG-OO1 and imatinib combination treatment showed the most significant reduction in total colony forming units (CFU) as compared to the control of either drug alone treatment in all samples (FIG. 21D). Furthermore, the morphological characteristics of the colonies also change after drug treatment; The colonies were smaller and dispersed, and the distributed colony phenotypes were more severe in the combination treatment, and the result indicates that the treated colonies had an increased differentiation. The control colonies were large and dense with distinct differences. The H & E staining showed a reduced nuclear / cytoplasmic ratio in the treated cells (FIG. 21E). Importantly, treatment of normal CD34 + cells with ICG-001 had minimal effects on total cellularity, CFU-Es and BFU-Es. ICG-001 had no effect on colony formation of normal CD34 + hematopoietic cells.

In summary, imatinib itself has a limited effect, but the combination of imatinib with IGC-001 has a significant additional effect. ICG-001 up to 20 μM showed no severe side effects on normal CD34 + cells and induced differentiation, but did not activate caspase in K562 cells.

Example  5

Stem cells Marker CD133  or Prominin Cultured ovaries expressing -1 carcinoma  And against melanoma cells ICG -001 and Cisplatin  effect

This example describes the measurement of the sensitivity of ovarian carcinoma cells to ICG-001.

Colony inhibition assays were performed by exposing cells plated from A2780, CP70, IGROV-I and B16 cells to doses of ICG-001 in the range of 0.625-10 μM. Representative experiments are described in Table 3.

As shown in Table 3, even at a concentration of 0.625 μM ICG-001, there was a statistically significant difference between the control group (media containing DMSO) and all experimental groups (media containing ICG-001 dissolved in DMSO).

Table 4 shows data for plate culture efficiency for cells cultured from A2780, CP70, IGROV-I and B16 in wells exposed to ICG-001 as well as control wells. The data indicate that the cell culture efficiency of the various cell lines was high, varied between 21% and 83%, and fits well with the fact that most of the plated cells expressed the CD133 marker of CSC.

The cells were tested at ICG-001 concentration ranges between 0.625-10 μM and cisplatin levels between 1.25-20 μM. All three ovarian cancer cell lines tested (A2780, CP70 and IGROV-1) were more sensitive to ICG-001 than cisplatin. For the cisplatin-resistant cell line CP70,> 90% inhibition was achieved at 5 μM of ICG-001 as compared to 20 μM of cisplatin (FIG. 23C). The cisplatin-sensitive cell lines, IGROV-I and A2780, had similar sensitivity to ICG-001 for cisplatin (FIGS. 23A and B). 24 shows experiments comparing the sensitivity of ovarian carcinoma cell lines to ICG-001 and cisplatin.

The cells were tested at ICG-001 concentration ranges between 0.625-10 μM and cisplatin levels between 1.25-20 μM. All three ovarian cancer cell lines tested (A2780, CP70 and IGROV-1) were more sensitive to ICG-001 than cisplatin. For the cisplatin-resistant cell line CP70,> 90% inhibition was achieved at 5 μM of ICG-001.

Example  6

SW480  In the cell CBP -β- Catenin  Suppression of interaction

The effect of some compounds on CBP-β-catenin binding was tested using a TOPFlash reporter system in SW480 cells.

As shown in FIG. 25, increasing concentrations of compounds PRI-OOl, PRI-002, PRI-003, PRI-004, PRI-005 and PRI-006 were effective as compared to ICG-001. FIG. 26 shows pluc-6270 expression (luciferase) in SW480 cells treated with various concentrations of ICG-001, PRI-003, and PRI-004.

All patents, patent applications, provisional applications, and publications mentioned or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent that they do not conflict with the explicit teachings of this specification.

Claims (98)

Compounds having the general formula (I), stereoisomers thereof, salts thereof, and prodrugs thereof:

Wherein A is-(C = O) -CHR ₃ -or-(C = O)-, B is NR ₅ -or -CHR _6- , and D is-(C = O)-(CHR ₇ )- Or-(C = O)-, E is-(ZR ₈ )-or-(C = O)-, G is-(XR ₉ ) n-,-(CHR ₁₀ )-(NR ₆ )-, -(C = O)-(XR ₁₂ )-,-(C = NWR ₁ )-,-(C = O)-, X- (C = O) -R ₁₃ , X- (C = O) -NR ₁₃ R ₁₄ , X- (SO ₂ ) -R ₁₃ , or X- (C = O) -OR ₁₃ , W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ )-, -CHR ₁₄ , (C = O)-(NR ₁₅ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X And Z is independently nitrogen or CH, n is 0 or 1; And R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is the same or different and is independently selected from an amino acid side chain moiety or a derivative thereof, a remainder of the molecule, a linker and a solid support, provided that B is Is CHR ₆ and W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ )-, -CHR ₁₄ , or (C = O)-(NR ₁₅ )- , G may be CHR ₉ , NR ₉ , (C═O) —CHR ₁₂ , (C═O) —NR ₁₂ , or no atoms at all. The method according to claim 1, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _1-4 alkyl, guanidino C _{2 - 5} alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or Hydroxide are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-C _{1- 4} alkyl, alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), bis phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -} to ₄ dialkylamino, halogen, _perfluoro-4 alkylamino, C ₁ C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where the substituents Amino, amidino, guanidino, hydrazino, Mithraic Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl are independently selected from one or more of the lock), pyrimidyl C _{1 - 4} alkyl, C _{1 -4} alkyl substituted pyrimidyl (where pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 - 4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl , C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), imidazole C _{1 - 4} alkyl, imidazole substituted already C _{1 - 4} alkyl (where the imidazole substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -} C _{1 4} alkylamino, C _1-4 dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one or more of methyl Are independently selected from a), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, , C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} would independently selected from the group consisting of _2-alkyl compounds, their Salts, and their prodrugs. The compound of claim 1, wherein A is-(CHR ₃ )-(C = 0)-, B is-(NR ₄ )-, D is-(C = 0)-, and E is-(ZR ₆ ) -, G is-(C = 0)-(XR ₉ )-, and a compound having the general formula (III):

Wherein Z is nitrogen or CH, and when Z is CH, X is nitrogen. The compound of claim 1, wherein A is —0-CHR ₃ —, B is —NR ₄ —, D is — (C═O) —, E is — (ZR ₆ ) —, and G is (XR _7). ) _n -and a compound having the general formula (IV), salts thereof, and prodrugs thereof:

Wherein, R ₁ , R ₂ , R ₄ , R ₆ , R ₇ , R ₈ , W, X and n are as defined above, Y is -C = O,-(C = O) -O-,-(C = O) -NR ₈ , -SO _2- , or absent, Z is nitrogen or CH (n is 0 when Z is nitrogen, X is nitrogen and Z is not 0 when Z is CH). The method according to claim 1, wherein A is-(C = O)-, B is-(CHR ₆ )-, D is-(C = O)-, E is-(ZR ₈ )-, G Is-(NH)-or-(CH ₂ )-, W is substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4, 5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, a compound having the general formula (V), a salt thereof, and a prodrug thereof :

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, J is nitrogen, oxygen, or sulfur, Z is nitrogen or CH, R ₁ , R ₂ , R ₆ , R ₈ And R ₁₃ is selected from the amino acid side chain moiety. Compounds having the general formula (VI), stereoisomers thereof, salts thereof, and prodrugs thereof:

Wherein B is-(CHR ₂ )-or-(NR ₂ )-, E is-(CHR ₃ )-, V is-(XR ₄ )-or absent, and W is-(C = O)- (XR ₅ R ₆ ),-(SO ₂ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydro Oxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen, oxygen, or CH, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are selected from amino acid side chain moieties or derivatives thereof. The method according to claim 1, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _1-4 alkyl, guanidino C _{2 - 5} alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or Hydroxide are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-C _{1- 4} alkyl, alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), bis phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -} to ₄ dialkylamino, halogen, _perfluoro-4 alkylamino, C ₁ C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where the substituents Amino, amidino, guanidino, hydrazino, Mithraic Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, Hydra if no, amido dryer Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), pyrimidyl C _{1 - 4} alkyl, C _{1 -4} alkyl substituted pyrimidyl (where pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 - 4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), imidazole C _{1 - 4} alkyl, C _{1 -4} already substituted imidazole alkyl (where the imidazole substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C ₁ to C _1-4 dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one or more of methyl coming Are independently selected from a), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, , C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} would independently selected from the group consisting of _2-alkyl compounds, their salt, And his prodrugs. The compound of claim 6, wherein B is-(CH)-(CH ₃ ), E is-(CH)-(CH ₃ ), V is-(XR ₄ )-or absent, and W is substituted or unsubstituted. Oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, or substituted Or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen or CH, a compound having the general formula (VII), a salt thereof, and His prodrug:

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, and J is nitrogen, oxygen, or sulfur. A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a salt thereof, and a prodrug thereof, and a pharmaceutically acceptable carrier:

Wherein A is-(C = O) -CHR ₃ -or-(C = O)-, B is NR ₅ -or -CHR _6- , and D is-(C = O)-(CHR ₇ )- Or-(C = O)-, E is-(ZR ₈ )-or-(C = O)-, G is-(XR ₉ ) n-,-(CHR ₁₀ )-(NR ₆ )-, -(C = O)-(XR ₁₂ )-,-(or absent)-,-(C = O)-, X- (C = O) -R ₁₃ , X- (C = O) -NR ₁₃ R ₁₄ , X- (SO ₂ ) -R ₁₃ , or X- (C = O) -OR ₁₃ , where W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ ) -, -CHR ₁₄ , (C = O)-(NR ₁₅ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4 , 5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X and Z Is independently nitrogen or CH, n is 0 or 1; And R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is the same or different and is independently selected from an amino acid side chain moiety or a derivative thereof, a remainder of the molecule, a linker and a solid support. The method according to claim 9, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _1-4 alkyl, guanidino C _{2 - 5} alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or Hydroxide are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-C _{1- 4} alkyl, alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), bis phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -} to ₄ dialkylamino, halogen, _perfluoro-4 alkylamino, C ₁ C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where the substituents Amino, amidino, guanidino, hydrazino, Mithraic Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl are independently selected from one or more of the lock), pyrimidyl C _{1 - 4} alkyl, C _{1 -4} alkyl substituted pyrimidyl (where pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 - 4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), imidazole C _{1 - 4} alkyl, C _{1 -4} already substituted imidazole alkyl (where the imidazole substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C ₁ to C _1-4 dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one or more of methyl coming Are independently selected from), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, , C ₁ - ₅ dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} a pharmaceutical composition which is independently selected from the group consisting of ₂ alkyl . The compound of claim 9, wherein A is-(CHR ₃ )-(C = 0)-, B is-(NR ₄ )-, D is-(C = 0)-, and E is-(ZR ₆ ) -, G is-(C = 0)-(XR ₉ )-, and the compound has the following general formula (III):

Wherein Z is nitrogen or CH, and when Z is CH, X is nitrogen. The compound of claim 9, wherein A is -0-CHR _3- , B is -NR _4- , D is-(C = O)-, E is-(ZR ₆ )-, and G is (XR ₇ ) A pharmaceutical composition wherein _n- and the compound has the general formula (IV)

Wherein Y is-(C = O)-,-(C = O) -O-,-(C = O) -NR ₈ , -SO _2- , or nothing, Z is nitrogen or CH ego; When Z is nitrogen, n is 0 and when Z is CH, X is nitrogen and n is not zero. The compound of claim 9, wherein A is-(C = O)-, B is-(CHR ₆ )-, D is-(C = O)-, E is-(ZR ₈ )-, and G is -(NH)-or-(CH ₂ )-, W is substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 A pharmaceutical composition which is dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, and the compound has the following general formula (V):

Wherein K is nitrogen, oxygen, or sulfur, L is nitrogen, oxygen,-(CH)-, or-(CH ₂ )-, J is nitrogen, oxygen, or sulfur, Z is nitrogen or CH, R ₁ , R ₂ , R ₆ , R ₈ And R ₁₃ is selected from the amino acid side chain moiety. A pharmaceutical composition comprising a compound having the formula (VI): a stereoisomer thereof, a salt thereof, and a prodrug thereof:

Wherein B is-(CHR ₂ )-or-(NR ₂ )-, E is-(CHR ₃ )-, V is-(XR ₄ )-or absent, and W is-(C = O)- (XR ₅ R ₆ ),-(SO ₂ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydro Oxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, X is independently nitrogen, oxygen, or CH, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are selected from amino acid side chain moieties or derivatives thereof. The method according to claim 14, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _1-4 alkyl, guanidino C _{2 - 5} alkyl, amino gavel C _{2 - 5} alkyl, C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl amidino _2- C ₅ alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (wherein the substituent is amino , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} independently selected from one or more of alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl, wherein the substituents on benzyl are amino, amidino, guanidino, hydrazino, amidara Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or Hydroxide are independently selected from one or more of the hydroxyl), naphthyl, substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-C _{1- 4} alkyl, alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), bis phenyl methyl, substituted bis-phenyl methyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -} to ₄ dialkylamino, halogen, _perfluoro-4 alkylamino, C ₁ C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} are independently selected from alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl, substituted pyridyl (where the substituents Amino, amidino, guanidino, hydrazino, Mithraic Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} alkyl, di-C _{1- 4} alkylamino, halogen, perfluoroalkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), pyridyl C _{1 - 4} alkyl, substituted pyridyl C _1-4 alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl , C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl are independently selected from one or more of the lock), pyrimidyl C _{1 - 4} alkyl, C _{1 -4} alkyl substituted pyrimidyl (where pyrimidine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl groups are independently selected from one or more of), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 - 4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _1-4 alkylamino, C _{1-C 1} to ₄ dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), imidazole C _{1 - 4} alkyl, C _{1 -4} already substituted imidazole alkyl (where the imidazole substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C ₁ to C _1-4 dialkylamino, halogen, _{perfluoro-4-alkyl,} C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, hydroxyl or one or more of methyl coming Are independently selected from a), imidazolinyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _1-5 alkylamino-C _{2 - 5} alkyl, , C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 - 4} alkyl and 4-amino-cyclohexyl-C _{0 -} a pharmaceutical composition which is independently selected from the group consisting of ₂ alkyl . The compound of claim 15, wherein B is-(CH)-(CH ₃ ), E is-(CH)-(CH ₃ ), V is-(XR ₄ )-or absent, and W is substituted or unsubstituted. Oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4,5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or A pharmaceutical composition having unsubstituted 4,5 dihydroimidazole, X is independently nitrogen or CH, and the compound has the general formula (VII)

Wherein K is nitrogen, oxygen, or sulfur, L is a nitrogen, oxygen, - (CH) -, or - (CH ₂₎ - and, J is nitrogen, oxygen, or sulfur, R ₅ is amino-C _{2 - 5} alkyl, guanidino C _{2 - 5} alkyl, C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, di-C _{1 - 4} alkyl, guanidino C _{2 - 5} alkyl, amidino C _{2 - 5} alkyl, C _{1 - 4} alkyl amidino _2- C ₅ alkyl, di-C _{1 - 4} alkyl, amidino C _{2 - 5} alkyl, C _{1 - 3} alkoxy, phenyl, substituted phenyl (where the substituents are amino, amidino, guanidino, hydrazino, amido drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano No, snow are independently selected from sulfuryl or at least one of the hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino , C _{1 - 4} Alkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), naphthyl , substituted naphthyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl , C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl or are independently selected from one or more of the hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} di-alkyl amino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 -} the unit ₃ alkoxy, nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl Is independently selected), pyridyl, substituted pyridyl (where the substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 -4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyridyl C _{1 - 4} alkyl , substituted pyridyl C _{1 -4} alkyl (where the pyridine substituents include amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro a C _{1 - 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, are independently selected from nitro, carboxy, cyano, sulfuryl or at least one of the hydroxyl), pyrimidyl C _{1- 4} alkyl, substituted a pyrimidyl C _{1 -4} alkyl (where the pyrimidine substituents are amino, amidino, guanidino, great La Gino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano no, sulfuryl or hydroxyl are independently selected from one or more of the hydroxyl), triazin-2-yl -C _{1 - 4} alkyl, substituted triazin-2-yl -C _{1 -4} alkyl (where the triazine substituents are amino, amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} with di-alkylamino, halogen, perfluoro-C _{1- 4} alkyl, C _{1 - 4} alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfonic are independently selected from one or more of sulfuryl or hydroxyl), imidazole C _{1 - 4} alkyl, optionally substituted imidazol-C _{1 -4} alkyl (wherein the substituent is an amino-imidazole , amidino, guanidino, hydrazino, amino drive Zonyl, C _{1 - 4} alkylamino, C _{1 - 4} dialkylamino, halogen, perfluoro A C _{1 - 4} alkyl, C _1-4 alkyl, C _{1 - 3} alkoxy, nitro, carboxy, cyano, sulfuryl, are independently selected from hydroxyl or one or more of methyl), and Jolly already carbonyl C _{1 - 4} alkyl, N- amidino piperazinyl ₀ -NC _{- 4} alkyl, hydroxy C _{2 - 5} alkyl, C _{1 - 5} alkyl-amino-C _{2 - 5} alkyl, C _{1 - 5} dialkylamino C _{2 - 5} alkyl, N- amidino piperidinyl C _{1 -} are independently selected from the group consisting of _{2-alkyl-4-alkyl} and 4-amino-cyclohexyl C _0. A compound selected from the group consisting of Compounds 1-2217. A pharmaceutical composition comprising one or more compounds of claim 17. The pharmaceutical composition of claim 9, wherein the composition comprises an effective amount of the compound and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 14, wherein the composition comprises an effective amount of the compound and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 18, wherein the composition comprises an effective amount of the compound and a pharmaceutically acceptable carrier. The compound of claim 17, wherein the compound is used in the manufacture of a medicament for eradicating pathological stem cells in cancer treatment. The compound of claim 22, wherein the stem cells are stem cells of leukemia. The compound of claim 22, wherein said stem cells are derived from a solid tumor. The compound of claim 24, wherein the solid tumor is selected from the group consisting of breast, brain, lung, colon, liver, and intestine. The composition of claim 21, wherein the therapeutically effective amount of the compound is an amount sufficient to cause cell death or inhibit proliferation and cause differentiation of stem cells in solid tumors or leukemias. 18. The compound of claim 17, wherein said compound is used in the manufacture of a medicament for achieving differentiation of pathological stem cells by causing the conversion from CBP / catenin transcription to p300 / catenin transcription in the treatment of cancer. 18. The compound of claim 17, wherein said catenin is β-catenin. The compound of claim 17, wherein the catenin is γ / p120-catenin. The compound of claim 17, wherein the compound inhibits CBP / catenin signaling in cancer stem cells. 31. The compound of claim 30, wherein said catenin is β-catenin. 31. The compound of claim 30, wherein said catenin is γ / p120-catenin. The compound of claim 17, wherein the compound inhibits CBP / catenin signaling in cancer stem cells, thereby inducing either cell cycle arrest and cell death or differentiation of cancer stem cells. The compound of claim 33, wherein the catenin is β-catenin. The compound of claim 33, wherein the catenin is γ / p120-catenin. The method of claim 17, wherein the compound inhibits CBP / catenin signaling in cancer stem cells, thereby inducing differentiation of cancer stem cells and making cancer stem cells more sensitive to apoptosis induced by one or more specific pathway inhibitors. Compound to make. The method of claim 36, wherein the specific pathway is selected from the group consisting of EGFR pathway; And Herceptin, Abl, or Kit tyrosine kinase pathway (imatinib). The compound of claim 36, wherein the catenin is β-catenin. The compound of claim 36, wherein the catenin is γ / p120-catenin. 18. The method of claim 17, wherein said compound achieves differentiation of pathological stem cells by causing the conversion from CBP / catenin transcription to p300 / catenin transcription in the treatment of cancer, whereby the cancer cells are further pathway-specific. A compound used for the manufacture of a medicament that makes it more sensitive to treatment by inhibitors. The method of claim 40, wherein the pathway-specific inhibitor is imatinib; Herl / Her2 inhibitor; Notch inhibitors; Hedgehog inhibitors; EGF inhibitors; And a PI3K pathway inhibitor. The compound of claim 41, wherein the Notch inhibitor is a gamma secretase inhibitor. 42. The compound of claim 41, wherein the Hedgehog inhibitor is cyclopamine. The compound of claim 41, wherein the EGF inhibitor is Iressa. The compound of claim 41, wherein the PI3K pathway inhibitor is rapamycin. The compound of claim 17, wherein the compound blocks CBP / β-catenin interaction. The compound of claim 17, wherein the compound blocks CBP / gamma-catenin (p120 catenin) interaction. The compound of claim 17, wherein the compound is delivered orally, transdermally, intravenously, topically, inhaled, or rectally to a subject. The compound of claim 17, wherein the compound is delivered orally. The compound of claim 17, wherein the compound is administered to the subject by sustained release. The method of claim 17, wherein the compound is selected from the group consisting of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, and suppositories. Administered by. A method of treating a cancerous condition by administering one or more compounds of claim 17, wherein the cancerous condition is acute lymphocytic leukemia, acute nonlymphocytic leukemia, adrenal cortical cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic Leukemia, Chronic Myeloid Leukemia, Colorectal Cancer, Cutaneous T Cell Lymphoma, Endometrial Cancer, Esophageal Cancer, Ewing's Sarcoma, Gallbladder Cancer, Hairy Cell Leukaemia, Head and Neck Cancer, Hodgkin's Lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or non-small cells), malignant peritoneal effusion, malignant pleural effusion , Melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, pancreatic cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, soft tissue sarcoma ( soft -tissue sarcoma), squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, and Wilm's tumor At least one selected. The method of claim 52, wherein the compound is delivered to the subject orally, transdermally, intravenously, topically, inhaled, or rectally. The method of claim 53, wherein the compound is delivered orally. The method of claim 53, wherein the compound is administered to the subject by sustained release. A group comprising one or more compounds of claim 17 and comprising capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, eye drops, and suppositories The pharmaceutical composition is administered by a method selected from. A pharmaceutical composition comprising one or more compounds of claim 17 in combination with one or more cancer chemotherapeutic agents acting by a mechanism other than blocking CBP / catenin interactions. The composition of claim 57, wherein the cancer therapeutic agent is selected from the group consisting of cis-platinum, retinoic acid, HDAC inhibitors, SAHA, and imatinib. Removing teratoma-forming stem cells prior to implantation into a mammalian subject, comprising culturing the stem cell culture with at least one compound of claim 17, wherein the compound is CBP-β-catenin Inhibiting the interaction, thereby causing the differentiation of stem cells. The pharmaceutical composition of claim 8, 14 or 18, wherein the compound is used in the manufacture of a medicament for eradicating pathological stem cells in cancer treatment. The pharmaceutical composition of claim 60, wherein the stem cells are stem cells of leukemia. The pharmaceutical composition of claim 61, wherein the stem cells are from a solid tumor. 63. The method of claim 62, wherein the solid tumor is breast, brain, lung, colon, liver, and intestine. Pharmaceutical composition is selected from the group consisting of. The pharmaceutical composition of claim 60, wherein the therapeutically effective amount of the compound is an amount sufficient to cause cell death or inhibit proliferation, and cause differentiation of stem cells in solid tumors or leukemias. The pharmaceutical composition of claim 60, wherein the compound is used in the manufacture of a medicament for achieving differentiation of pathological stem cells by causing the conversion from CBP / catenin transcription to p300 / catenin transcription in the treatment of cancer. The pharmaceutical composition of claim 65, wherein the catenin is β-catenin. The pharmaceutical composition of claim 65, wherein the catenin is γ / p120-catenin. The pharmaceutical composition of claim 60, wherein the compound inhibits CBP / catenin signaling in cancer stem cells. The pharmaceutical composition of claim 68, wherein the catenin is β-catenin. The pharmaceutical composition of claim 68, wherein the catenin is γ / p120-catenin. The pharmaceutical composition of claim 60, wherein the compound inhibits CBP / catenin signaling in cancer stem cells, thereby inducing either cell cycle arrest and cell death or differentiation of cancer stem cells. The pharmaceutical composition of claim 71, wherein the catenin is β-catenin. The pharmaceutical composition of claim 71, wherein the catenin is γ / p120-catenin. The method of claim 60, wherein the compound inhibits CBP / catenin signaling in cancer stem cells, thereby inducing differentiation of cancer stem cells and making cancer stem cells more sensitive to apoptosis induced by one or more specific pathway inhibitors. Pharmaceutical composition. The method of claim 74, wherein the specific pathway is selected from the group consisting of EGFR pathway; And Herceptin, Abl, or Kit tyrosine kinase pathway (imatinib). The pharmaceutical composition of claim 74, wherein the catenin is β-catenin. The pharmaceutical composition of claim 74, wherein the catenin is γ / p120-catenin. The method of claim 60, wherein the compound achieves the differentiation of pathological stem cells by causing the conversion from CBP / catenin transcription to p300 / catenin transcription in the treatment of cancer, whereby the cancer cells are directed to other pathway-specific inhibitors. A pharmaceutical composition for use in the manufacture of a medicament that makes it more sensitive to treatment by. The method of claim 78, wherein the pathway-specific inhibitor is imatinib; Herl / Her2 inhibitor; Notch inhibitors; Hedgehog inhibitors; EGF inhibitors; And a PI3K pathway inhibitor. The pharmaceutical composition of claim 79, wherein the Notch inhibitor is a gamma secretase inhibitor. The pharmaceutical composition of claim 79, wherein the Hedgehog inhibitor is cyclopamine. The pharmaceutical composition of claim 79, wherein the EGF inhibitor is Iressa. The pharmaceutical composition of claim 60, wherein the PI3K pathway inhibitor is rapamycin. The pharmaceutical composition of claim 60, wherein the compound blocks CBP / β-catenin interaction. The pharmaceutical composition of claim 60, wherein the compound blocks CBP / gamma-catenin (p120 catenin) interaction. The pharmaceutical composition of claim 60, wherein the compound is delivered to the subject orally, transdermally, intravenously, topically, inhaled, or rectally. The pharmaceutical composition of claim 86, wherein the compound is delivered orally. The pharmaceutical composition of claim 60, wherein the compound is administered to the subject by sustained release. The method of claim 60, wherein the pharmaceutical composition is selected from the group consisting of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, and suppositories. Composition to be administered. 60. A method of treating a cancerous condition by administering at least one pharmaceutical composition of claim 60, wherein the cancerous condition is acute lymphocytic leukemia, acute nonlymphocytic leukemia, adrenal cortical cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, Chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukaemia, head and neck cancer, Hodgkin's lymphoma (hodgkin's) lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and / or non-small cells), malignant peritoneal effusion, malignant pleural effusion pleural effusion), melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovarian (germ cell) cancer, pancreatic cancer, penile cancer, prostate cancer, retinoblastoma, skin cancer, Soft Soft-tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, and Wilm's tumor At least one selected from the group consisting of: The method of claim 90, wherein the pharmaceutical composition is delivered to the subject orally, transdermally, intravenously, topically, inhaled, or rectally. The method of claim 90, wherein the pharmaceutical composition is delivered orally. The method of claim 90, wherein the pharmaceutical composition is administered to the subject by sustained release. The group of claim 60, wherein the pharmaceutical composition is comprised of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, eye drops, and suppositories. The pharmaceutical composition is administered by a method selected from. A pharmaceutical composition comprising one or more compounds of claim 60 in combination with one or more cancer chemotherapeutic agents acting by a mechanism other than blocking CBP / catenin interaction. The composition of claim 95, wherein the cancer therapeutic agent is selected from the group consisting of cis-platinum, retinoic acid, HDAC inhibitors, SAHA, and imatinib. Teratoma before transplantation into a mammalian subject, including culturing the stem cell culture with one or more compounds of claim 17 that inhibit CBP-β-catenin interaction and thereby cause stem cell differentiation. How to get rid of forming stem cells. A method of removing teratoma-forming stem cells prior to transplantation into a mammalian subject, comprising: a stem cell culture with a compound of formula (I), a stereoisomer thereof, a salt thereof, and a prodrug thereof Method comprising culturing:

Wherein A is-(C = O) -CHR ₃ -or-(C = O)-, B is NR ₅ -or -CHR _6- , and D is-(C = O)-(CHR ₇ )- Or-(C = O)-, E is-(ZR ₈ )-or-(C = O)-, G is-(XR ₉ ) n-,-(CHR ₁₀ )-(NR ₆ )-, -(C = O)-(XR ₁₂ )-,-(or absent)-,-(C = O)-, X- (C = O) -R ₁₃ , X- (C = O) -NR ₁₃ R ₁₄ , X- (SO ₂ ) -R ₁₃ , or X- (C = O) -OR ₁₃ , where W is -Y (C = O)-,-(C = O) NH-,-(SO ₂ ) -, -CHR ₁₄ , (C = O)-(NR ₁₅ )-, substituted or unsubstituted oxadiazole, substituted or unsubstituted triazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted 4 , 5 dihydrooxazole, substituted or unsubstituted 4,5 dihydrothiazole, substituted or unsubstituted 4,5 dihydroimidazole, or nothing, Y is oxygen or sulfur, X and Z Is independently nitrogen or CH, n is 0 or 1; And R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ And R ₁₅ is the same or different and is independently selected from an amino acid side chain moiety or a derivative thereof, a remainder of the molecule, a linker and a solid support.

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